Tricyclic diazepine vasopressin antagonists and oxytocin antagonists

ABSTRACT

Tricyclic diazepines of the formula: ##STR1## wherein A, B, D, E, F, Y and Z are defined in the specification which compounds have vasopressin and oxytocin antagonist activity.

This application is a division of Ser. No. 08/999,830, filed Oct. 3, 1997, which is a continuation of Ser. No. 08/646,653, filed May 8, 1996, now abandoned, which is a continuation-in-part of Ser. No. 08/468,737, filed Jun. 6, 1995, now U.S. Pat. No. 5,624,923, which is a division of Ser. No. 08/254,822, filed Jun. 13, 1994, now U.S. Pat. No. 5,516,774, which is a continuation-in-part of Ser. No. 08/100,004, filed Jul. 29, 1993, now abandoned.

FIELD OF THE INVENTION

This invention relates to new tricyclic non-peptide vasopressin antagonists which are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and conditions with increased vascular resistance and coronary vasoconstriction.

BACKGROUND OF THE INVENTION

Vasopressin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain osmoreceptors or decreased blood volume and blood pressure sensed by low-pressure volume receptors and arterial baroreceptors. The hormone exerts its actions through two well defined receptor subtypes: vascular V₁ and renal epithelial V₂ receptors. Vasopressin-induced antidiuresis, mediated by renal epithelial V₂ receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased. V₁ antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induced increases in total peripheral resistance and altered local blood flow, V₁ -antagonists may be therapeutic agents.

The blockade of V₂ receptors may be useful in treating diseases characterized by excess renal reabsorption of free water. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific receptors on renal collecting tubule cells. This binding stimulates adenylyl cyclase and promotes the cAMP-mediated incorporation of water pores into the luminal surface of these cells. V₂ antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive heart failure which is more common in older patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopressin levels, a V₂ antagonist may be beneficial in promoting free water excretion by antagonizing the action of antiduretic hormone. On the basis of the biochemical and pharmacological effects of the hormones antagonists of vasopressin are expected to be therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephrotic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding, abnormal states of water retention.

The following prior art references describe peptide vasopressin antagonists; M. Manning et al., J. Med. Chem., 11, 382(1992); M. Manning et al., J. Med. Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Pat. No. 5,070,187 (1991); M. Manning and W. H. Sawyer, U.S. Pat. No. 5,055,448(1991); F. E. Ali, U.S. Pat. No. 4,766,108(1988); R. R. Ruffolo et al., Drug News and Perspective, 4(4), 217, (May)(1991). P. D. Williams et al., have reported on potent hexapeptide oxytocin antagonists [J. Med. Chem., 35, 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to V₁ and V₂ receptors. Peptide vasopressin antagonists suffer from a lack or oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Br. J. Pharmacol., 105, 787(1992), Ogawa et al., (Otsuka Pharm Co., LTD.) EP 0514667-A1; JP 04154765-A; EPO 382185-A2; and W09105549. Carbostyril derivatives and pharmaceutical compositions containing the same are disclosed by Ogawa et al., (Otsuka Pharm. Co.) in EP 470514A. Non-peptide oxytocin and vasopressin antagonist have been disclosed by Merck and Co.; M. G. Bock and P. D. Williams, EP 0533242A; M. G. Bock et al., EP 0533244A; J. M. Erb, D. F. Verber, P. D. Williams, EP0533240A; K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the prevention of preterm labor, B. E. Evans et al., J. Med. Chem., 35, 3919(1992), J. Med. Chem., 36, 3993(1993) and references therein. The compounds of this invention are antagonists of the peptide hormone oxytocin and are useful in the control of premature birth.

The present invention relates to novel tricyclic derivatives which exhibit antagonist activity at V₁ and/or V₂ receptors and exhibit in vivo vasopressin antagonist activity. The compounds also exhibit antagonists activity of oxytocin receptors.

SUMMARY OF THE INVENTION

This invention relates to new compounds selected from those of the general formula I: ##STR2## wherein Y is a moiety selected from; --(CH₂)_(n) -- wherein n is an integer from 0 to 2, ##STR3## A-B is a moiety selected from ##STR4## wherein m is an integer from 1 to 2 provided that when Y is --(CH₂)_(n) -- and n is 2, m may also be zero and when n is zero, m may also be three, provided also that when Y is --(CH₂)_(n) -- and n is 2, m may not be two;

and the moiety: ##STR5## represents: (1) fused phenyl or fused substituted phenyl optionally substituted by one or two substituents selected from (C₁ -C₃)lower alkyl, halogen, amino, (C₁ -C₃)lower alkoxy or (C₁ -C₃)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C₁ -C₃)lower alkyl, halogen or (C₁ -C₃)lower alkoxy;

the moiety: ##STR6## is a five membered aromatic(unsaturated) fused nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C₁ -C₃)lower alkyl, hydroxy, --COCl₃, --COCF₃, ##STR7## --CHO, amino, (C₁ -C₃)lower alkoxy, (C₁ -C₃)lower alkylamino, CONH-lower alkyl(C₁ -C₃), and --CON[lower alkyl(C₁ -C₃)]₂ ; q is one or two; R_(b) is independently selected from hydrogen, --CH₃ or --C₂ H₅ ; R³ is a moiety of the formula: ##STR8## wherein Ar is a moiety selected from the group consisting of ##STR9## wherein X is selected from O, S, NH, NCH₃ and NCOCH₃ ; R⁴ is selected from hydrogen, lower alkyl(C₁ -C₃), --CO-lower alkyl(C₁ -C₃), ##STR10## --SO₂ lower alkyl(C₁ -C₃); R¹ and R² are selected from hydrogen, (C₁ -C₃)lower alkyl, (C₁ -C₃)lower alkoxy and halogen; R⁵ is selected from hydrogen, (C₁ -C₃)lower alkyl, (C₁ -C₃)lower alkoxy and halogen; R⁶ is selected from (a) moieties of the formulae: ##STR11## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, --CH₃, --C₂ H₅, ##STR12## --(CH₂)_(q) --O-lower alkyl(C₁ -C₃) and --CH₂ CH₂ OH, q is one or two, and R₁, R₂ and R_(b) are as hereinbefore defined;

(b) a moiety of the formula: ##STR13## wherein R is as hereinbefore defined; (c) a moiety of the formula: ##STR14## wherein J is R_(a), lower alkyl(C₁ -C₈) branched or unbranched, lower alkenyl(C₁ -C₈) branched or unbranched, O-lower alkyl(C₁ -C₈) branched or unbranched, --O-lower alkenyl(C₁ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ --K wherein K is (C₁ -C₃) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR15## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl(C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, --CO₂ -lower alkyl(C₁ -C₃), and R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety of the formula: ##STR16## wherein R_(a) and R_(b) are as hereinbefore defined and Ar' is selected from moieties of the formula: ##STR17## wherein W' is selected from O, S, NH, N-lower alkyl(C₁ -C₃), NHCO-lower alkyl(C₁ -C₃), and NSO₂ lower alkyl(C₁ -C₃);

R⁷ is selected from hydrogen, lower alkyl(C₁ -C₃), halogen, O-lower alkyl(C₁ -C₃) and CF₃ ; R⁸ and R⁹ are independently selected from hydrogen, lower alkyl(C₁ -C₃), --S-lower alkyl(C₁ -C₃), halogen, --NH-lower alkyl(C₁ -C₃), --OCF₃, --OH, --CN, --S-CF₃, --NO₂, --NH₂, O-lower alkyl(C₁ -C₃), ##STR18## and CF₃ and; R¹⁰ is selected from hydrogen, halogen and lower alkyl(C₁ -C₃), and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Within the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R₃ is the moiety: ##STR19## and Ar is selected from the moiety ##STR20## wherein R⁵, R⁶ and R⁷ are as hereinbefore defined.

Especially preferred are compounds wherein R³ is the moiety ##STR21## Ar is selected from the moiety ##STR22## R⁶ is ##STR23## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(a) and R_(b) are as hereinbefore defined; and Ar' is selected from the moieties: ##STR24## wherein R⁸, R⁹ and W' are as hereinbefore defined.

Also especially preferred are compounds wherein Y in Formula I is --(CH₂)_(n) -- and n is zero or one; A-B is ##STR25## and R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are as hereinbefore defined; and m is an integer from 1-2.

The most preferred of the compounds of Formula I are those wherein Y is --(CH₂)_(n) -- and n is one; A-B is ##STR26## R₃ is the moiety ##STR27## Ar is the moiety ##STR28## R⁶ is ##STR29## --(CH₂)_(n) -cycloalkyl wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(a) and R_(b) are as hereinbefore defined; and Ar' is ##STR30## wherein R⁵, R⁸ and R⁹ are as previously defined.

The most highly broadly preferred of the compounds of Formula I are those wherein Y is --(CH₂)_(n) -- and n is zero or one; wherein the moiety ##STR31## is a fused phenyl, substituted phenyl, thiophene, furan, pyrrole or pyridine ring; A-B is ##STR32## m is one when n is one and m is two when n is zero; D, E, F, R¹, R², R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰, are as previously defined; R₃ is the moiety ##STR33## wherein Ar is ##STR34## and R₆ is selected from the group ##STR35## where Ar' is selected from the group ##STR36## and W', R_(a), R_(b) and cycloalkyl are as previously described.

More particularly preferred are compounds of the formulae: ##STR37## wherein the moiety: ##STR38## is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring; R³ is the moiety: ##STR39## wherein Ar is the moiety: ##STR40## R⁶ is ##STR41## and Ar' is selected from the moieties: ##STR42## wherein R_(a), R_(b), R⁵, R⁷, R⁸, R⁹, cycloalkyl and W' are as hereinbefore described; R¹¹ is selected from hydrogen, halogen, (C₁ -C₃) lower alkyl, hydroxy, ##STR43## --CHO, and (C₁ -C₃)lower alkoxy; and R¹² is selected from hydrogen, (C₁ -C₃)lower alkyl, halogen and (C₁ -C₃)lower alkoxy.

Also particularly preferred are compounds of the formulae: ##STR44## wherein m is one or two;

the moiety: ##STR45## is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring; R³ is the moiety: ##STR46## wherein Ar is the moiety: ##STR47## R⁶ is ##STR48## (CH₂)_(n) cycloalkyl; Ar' is selected from the moieties: ##STR49## wherein R_(a), R_(b), R⁵, R⁶, R⁸, R⁹, cycloalkyl and W' are as hereinbefore defined; R¹¹ is selected from hydrogen, halogen, (C₁ -C₃) lower alkyl, hydroxy, ##STR50## --CHO, and (C₁ -C₃)lower alkoxy; and R¹² is selected from hydrogen, (C₁ -C₃)lower alkyl, halogen and (C₁ -C₃)lower alkoxy.

More particularly preferred are compounds of the formulae: ##STR51## R³ is the moiety: ##STR52## wherein Ar is the moiety: ##STR53## R⁶ is ##STR54## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(b) is hydrogen; R_(a) is independently selected from hydrogen, --CH₃, --C₂ H₅ or --(CH₂)_(q) N(CH₃)₂ ; Ar' is selected from the moieties: ##STR55## wherein q, R_(a), R_(b), R⁵, R⁷, R⁸, R⁹, R¹¹ and W' are as hereinbefore described; R¹² and R¹³ are independently selected from hydrogen, (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy or (C₁ -C₃) lower alkylamino.

Also particularly preferred are compounds of the formulae: ##STR56## wherein m is one or two; R³ is the moiety: ##STR57## wherein Ar is the moiety: ##STR58## R⁶ is ##STR59## wherein cycloalkyl is defined as C₃ -C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; R_(b) is hydrogen; R_(a) is independently selected from hydrogen, --CH₃, --C₂ H₅ or --(CH₂)_(q) N(CH₃)₂ ; and Ar' is selected from the moieties: ##STR60## wherein q, R⁵, R⁷, R⁸, R⁹, R¹¹ and W' are as hereinbefore defined; R¹² and R¹³ are independently selected from hydrogen, (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃)lower alkoxy or (C₁ -C₃)lower alkylamino.

Among the more preferred compounds of this invention are those selected from Formula I: ##STR61## wherein;

A-B is ##STR62## wherein m is one or two;

the moiety ##STR63## represents a fused pyridine ring or fused substituted pyridine ring optionally substituted by one or two substituents selected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;

the moiety: ##STR64## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is carbon or nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C₁ -C₃) lower alkyl, hydroxy, COCCl₃, COCF₃, ##STR65##

R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR66## wherein Ar is a moiety selected from the group ##STR67## and X is selected from O, S, NH, --NCH₃, or --NCOCH₃ ;

R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR68##

R₁ and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR69## wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR70##

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR71## where R₂ is as hereinbefore defined; (c) a moiety of the formula: ##STR72## wherein J is R_(a), lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ -K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR73## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR74## wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl (C₁ -C₃), OH ##STR75##

q is 1 or 2;

R_(a) and R_(b) are as hereinbefore defined; wherein Ar' is selected from the group: ##STR76## wherein

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl (C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl (C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃), --OCF₃, --CN, --OH, --S-CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);

and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

Within the group above are the following preferred sub-groups 1 to 5 of compounds:

1. wherein R³ is the moiety: ##STR77## and Ar is the moiety ##STR78## wherein R⁵, R⁶, and R⁷ are as defined in claim 1 or a pharmaceutically acceptable salt, ester or pro-drug form thereof.

2. compounds of the formula: ##STR79## and Ar is the moiety ##STR80## wherein R⁵, R⁶, and R⁷ are as defined in claim 1 and Ar' is selected from the moieties ##STR81## wherein R⁵, R⁸, R⁹ and W' are as defined in claim 1, or a pharmaceutically acceptable salt, ester or pro-drug form thereof.

3. compounds of the formula: ##STR82## and Ar is the moiety ##STR83## wherein R⁵ and R⁷ are as defined in claim 1 and R⁶ is selected from:

(a) moieties of the formula: ##STR84## wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR85##

q is 1 or 2;

R_(b) is selected from H, --CH₃, or C₂ H₅ ; or

(b) a moiety of the formula: ##STR86## wherein J is R_(a), lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ -K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR87## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined; or

(c) a moiety selected from those of the formulae: ##STR88## wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl (C₁ -C₃), OH, ##STR89##

q is 1 or 2; and R_(a) and R_(b) are as hereinbefore defined; wherein Ar' is selected from the group: ##STR90## wherein R⁸, R⁹ and W' are as defined in claim 1, or a pharmaceutically acceptable salt, ester or pro-drug form thereof.

4. compounds of the formula: ##STR91## wherein;

A-B is ##STR92## wherein m is one;

the moiety ##STR93## represents a fused pyridine ring or fused substituted pyridine ring optionally substituted by one or two substituents selected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;

the moiety: ##STR94## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is carbon or nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C₁ -C₃) lower alkyl, hydroxy, COCCl₃, COCF₃, ##STR95##

R_(b) is independently selected from H, --CH₃, or --CH₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR96## wherein Ar is a moiety selected from the group ##STR97## and X is selected from O, S, NH, --NCH₃, or --NCOCH₃ ;

R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR98##

R₁ and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR99## wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR100##

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR101## where R₂ is as hereinbefore defined; (c) a moiety of the formula: ##STR102## wherein J is R_(a), lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ -K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR103## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR104## wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl (C₁ -C₃), OH ##STR105##

q is 1 or 2;

R_(a) and R_(b) are as hereinbefore defined; wherein Ar' is selected from the group: ##STR106## wherein

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl (C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl (C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃), --OCF₃, --CN, -OH, --S-CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃); and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

5. compounds of the formula: ##STR107## wherein;

A-B is ##STR108## wherein m is two;

the moiety ##STR109## represents a fused pyridine ring or fused substituted pyridine ring optionally substituted by one or two substituents selected from (C₁ -C₃) lower alkyl, halogen, amino, (C₁ -C₃) lower alkoxy, or (C₁ -C₃) lower alkylamino;

the moiety: ##STR110## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is carbon or nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C₁ -C₃) lower alkyl, hydroxy, COCCl₃, COCF₃, ##STR111##

R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ;

q is 1 or 2;

R₃ is the moiety ##STR112## wherein Ar is a moiety selected from the group ##STR113## and X is selected from O, S, NH, --NCH₃, or --NCOCH₃ ;

R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR114##

R₁ and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy, or halogen;

R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen;

R₆ is selected from:

(a) moieties of the formula: ##STR115## wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl;

n is 0-2;

R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR116##

R_(b) is as hereinbefore defined;

q is 1 or 2;

(b) a moiety of the formula: ##STR117## where R₂ is as hereinbefore defined; (c) a moiety of the formula: ##STR118## wherein J is R_(a), lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR119## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and

R_(a) and R_(b) are as hereinbefore defined;

(d) a moiety selected from those of the formulae: ##STR120## wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl (C₁ -C₃), OH ##STR121##

q is 1 or 2;

R_(a) and R_(b) are as hereinbefore defined; wherein Ar' is selected from the group: ##STR122## wherein

W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl (C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃);

R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl (C₁ -C₃), or CF₃ ;

R⁸ and R⁹ are independently selected from hydrogen, lower alkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃), --OCF₃, --CN, --OH, --S-CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃);

R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃); and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

Among the more preferred compounds of this invention are those selected from:

N-[4-(5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-11(10H)-ylcarbonyl)phenyl]-2-methyl-5-fluorobenzamide.

N-[4-(5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-11(10H)-ylcarbonyl)-3-chlorophenyl]-2-methyl-5-fluorobenzamide.

N-[4-(5H-pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-11(10H)-ylcarbonyl)-3-methylphenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepin-5(11H)-ylcarbonyl)phenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepin-5(11H)-ylcarbonyl)-3-chlorophenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepin-5(11H)-ylcarbonyl)-3-methylphenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepin-5(11H)-ylcarbonyl)-3-chlorophenyl]-2-chlorobenzamide.

N-[4-(6H-pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepin-5(11H)-ylcarbonyl)phenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepin-5(11H)-ylcarbonyl)-3-chlorophenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepin-5(11H)-ylcarbonyl)-3-methylphenyl]-2-methyl-5-fluorobenzamide.

N-[4-(6H-pyrazolo[1,5-a]pyrido[3,2-e][1,4]diazepin-5(11H)-ylcarbonyl)-3,6-dimethylphenyl]-2-methyl-5-fluorobenzamide.

Compounds of this invention may be prepared as shown in Scheme I by reaction of tricyclic derivatives of Formula 3a and 3b with a substituted or unsubstituted 4-nitrobenzoyl chloride 4 to give the intermediates 5a and 5b. Reduction of the nitro group in intermediates 5a and 5b gives the 4-aminobenzoyl derivatives 6a and 6b . The reduction of the nitro group in intermediates 5a and 5b may be carried out under catalytic reduction conditions (hydrogen-Pd/C; Pd/C- hydrazine-ethanol) or under chemical reduction conditions (SnCl₂ -ethanol; Zn-acetic acid; TiCl₃) and related reduction conditions known in the art for converting a nitro group to an amino group. The conditions for conversion of the nitro group to the amino group are chosen on the basis of compatability with the preservation of other functional groups in the molecule.

Reaction of compounds of Formula 6a and 6b with aroyl chloride or related activated aryl carboxylic acids in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine and diisopropylethylamine or pyridine and the like, affords the compounds 8a and 8b which are vasopressin antagonists. ##STR123##

Reaction of tricyclic derivatives of Formula 6a and 6b with either a carbamoyl derivative 9 or a isocyanate derivative 10 gives compounds (Scheme 2) of Formula 11a and 11b which are vasopressin antagonists of Formula I wherein R⁶ is ##STR124##

Reaction of tricyclic derivatives of Formula 6a and 6b with arylacetic acids, activated as the acid chlorides 12, anhydrides, mixed anhydrides or activated with known activating reagents, gives compounds 13a and 13b (Scheme 3). ##STR125##

The compounds of Formula I wherein Y, A-B, Z, R¹, R² and R³ are as defined and the Ar moiety of R³ (--COAr) is ##STR126## may be prepared, as shown in Scheme 4, by reacting an activated ester of the indole-5-carboxylic acids 14 with tricyclic derivatives 3a and 3b. The indole-5-carboxylic acids 14 may be activated by preparing the anhydride, a mixed anhydride or reacting with diethyl cyanophosphonate, N,N-carbonyldiimidazole or related peptide coupling reagents. As an example, the derivative 15 may be prepared by the acid 14 and N,N-carbonyldiimidazole in tetrahydrofuran; the solvent is removed and the derivative reacted with 3a or 3b at 100° C. to 120° C. without a solvent. Alternatively, 3a and 3b may be reacted with 15 in a solvent such as toluene or xylene at reflux temperatures. The activating reagent for the indole acids 14 is chosen on the basis of its compatibility with the R⁴ group and its reactivity with the tricyclic derivatives 3a and 3 b to give the vasopressin antagonists 16a and 16b. ##STR127##

The compounds of Formula I wherein Y, A-B, Z, R¹, R² and R³ are as defined and the Ar moiety of R³ (--COAr) is ##STR128## wherein R⁶ is ##STR129## may be prepared as shown in Scheme 5 by first converting derivatives 8a and 8b into the intermediates 17a and 17b and then reacting these intermediates with sodium or lithium azide to give the products 18a and 18b. ##STR130##

Alternatively, the products 18a and 18b may be prepared by coupling tetrazole derivatives of the Formula 19 with tricyclic derivatives 3a and 3b (Scheme 6). The tetrazole carboxylic acids are activated for coupling to the tricyclic compounds 3a and 3b by reaction with peptide coupling reagents, by conversion to the acid chlorides, anhydrides or mixed anhydrides. ##STR131##

As an alternative method for synthesis of compounds of this invention as depicted in Formula I wherein Y, A-B, D, E, F and Z are as previously described and R³ is ##STR132## is the coupling of aryl carboxylic acids 20 with the tricyclic derivatives 3a and 3b to give 21a and 21b.

The aryl carboxylic acids are activated for coupling by conversion to an acid chloride, bromide or anhydride or by first reacting with an activating reagent such as N,N-dicyclocarbodiimide, diethyl cyanophosphonate and related "peptide type" activating reagents. The method of activating the acids 20 for coupling to the tricyclic derivatives 3a and 3b is chosen on the basis of compatibility with other substituent groups in the molecule. The method of choice is the conversion of the aryl carboxylic acids 20 to the corresponding aroyl chloride. The aryl acid chlorides 22 may be prepared by standard procedures known in the art, such as reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydrofuran dioxane in the presence of pyridine or tertiary bases such as triethylamine and the like (Scheme 7). Alternatively, the aroyl chlorides 22, prepared from the aryl carboxylic acids 20, may be reacted with derivatives 3a and 3b in pyridine with or without 4-(dimethylamino)pyridine.

In general, when the aryl carboxylic acids 20 are activated with N,N-carbonyldiimidazole and other "peptide type" activating reagents, higher temperatures are required than when the aroyl chlorides are used. The reaction may be carried out in a higher boiling solvent xylene or without a solvent (100° C. to 150° C.). ##STR133## The starting materials 3a and 3b in the foregoing Schemes 1-7 may be prepared as follows. In accordance with Scheme 8, alkylation of heterocycles of structural type 24 with an alkylating moiety such as 23 gives intermediates 25. The heterocycle 24 may contain an α-carboxaldehyde function or an α-carboxylic and/or ester function as shown in Scheme 8. Where the intermediate 25 (R¹⁵ =H) contains an α-carboxaldehyde group, hydrogenation with palladium-on-carbon gives reduction and ring closure in one step to give 29.

In derivatives 25 where R¹⁵ is an α-carboxylic and/or an α-carboxylic ester function, the intermediate amino acid derivative 27 is first isolated and then ring closed. The ring closure of derivatives 27 may be carried out by heating or by activation of the acid function (27:R¹⁵ =H) for ring closure. The cyclic lactams 28 are conveniently reduced with diborane or lithium aluminum hydride to give intermediates 29. Reaction of tricyclic-derivatives 29 with aroyl chlorides (ArCOCl), where Ar is as hereinbefore defined, gives diazepines 26.

Tricyclic derivatives of structural type 36 may be prepared as shown in Scheme 9. Formylation of 32 under known conditions in the literature, such as Vilsmeier formylation, gives intermediates 35 which on reduction and ring closure affords tricyclics 37.

Where Z is a fused substituted or unsubstituted phenyl group, the procedure gives pyrrolo[1,2-a] quinoxalines 36. These derivatives 36 and 37 may be reacted with aroyl chlorides (ArCOCl) wherein Ar is as previously defined or with a substituted or unsubstituted 4-nitrobenzoyl chloride or with a nitrogen protecting group, such as benzyloxycarbonyl chloride to give compounds 38 and 39. The compounds 38 and 39 may be reacted with chlorine, bromine or halogenating reagents such as N-chlorosuccinimide, N-bromosuccinimide and the like to give compounds 40 and Al wherein R¹⁷ is a halogen atom. The derivatives 38 and 39 may be formylated and acetylated to give products 40 and 41 wherein R¹⁷ is a CHO or a --COCH₃ group. Halogenation, formylation and acetylation of derivatives 36 gives 1-substituted pyrrolo[1,2-a]quinoxalines. The derivatives 38, 39, 40 and 41 wherein R¹⁶ is a substituted or unsubstituted 4-nitrobenzoyl group are reduced to give the 4-aminobenzoyl derivatives 42d and 43d which are reacted with reagents Ar'COCl, Ar'CH₂ COCl or ##STR134## wherein Ar' and R_(b) are as previously hereinbefore defined, to give tricyclic diazepines 44 and 45. ##STR135##

The compounds of this invention wherein R³ is the moiety: ##STR136## and the Ar group is the moiety: ##STR137## and R⁶ is a ##STR138## group, wherein R_(a), R⁵, R⁷ and Ar' are as previously hereinbefore defined, are synthesized as shown in Scheme 10. The tricyclic derivatives 46 and 47 are reacted with the mono methyl terephthaloyl chloride 48 to give the aroylated methyl ester compounds 49 and 50. Hydrolysis of the methyl esters 49 and 50 gives the acids 51 and 52 which are activated for coupling by conversion to an activated ester or converted to the acid chlorides 53 and 54. Reaction of the acid chlorides 53 and 54 with the amines, ##STR139## wherein R_(a) and Ar' are as hereinbefore defined gives the derivatives 55 and 56. ##STR140##

Preparation of some tricyclic diazepines useful for starting materials for the synthesis of compounds of this invention are shown in Schemes 8 and 9. Other tricyclic diazepines are prepared by literature procedures or by methods known in the art or by procedures reported for the synthesis of specific known tricyclic diazepines. These diazepine ring systems discussed below when subjected to reaction conditions shown in Schemes 1, 2, 3, 4, 5, 6, 7, 9 and 10 give the compounds of this invention.

The tricyclic diazepine ring system, 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, ##STR141## is reported by G. Stefancich, R. Silvestri and M. Artico, J. Het. Chem. 30, 529(1993); ring substitution on the same ring system is reported by G. Stefancich, M. Artico, F. Carelli, R. Silvestri, G. deFeo, G. Mazzanti, I. Durando, M. Palmery, IL Farmaco, Ed. Sc., 40, 429(1985). ##STR142##

The synthesis of 9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepin-9-one ##STR143## is reported by F. Povazunec, B. Decroix and J. Morel, J. Het. Chem. 29, 1507(1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepine. ##STR144## The tricyclic 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]-benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, J. Het. Chem., 20, 871(1983); ##STR145## The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo [1,2-a]-thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 129, 360(1992); ##STR146## and is reduced with boron-dimethylsulfide to give 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. ##STR147## Also reported by A. Daich and B. Decroix is 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine ##STR148## which is also reduced to give 4,10-dihydro-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine ##STR149## Reported by B. Decroix and J. Morel, J. Het. Chem., 28, 81(1991) are pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine; ##STR150## and pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine. Reduction by hydrogen-Pd/c or chemical reduction with reagents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles ##STR151##

The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1, 2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R. Giuliano and M. Artico, IL Farmaco, Ed. Sc., 32, 339(1977). Annelated 1,5-benzodiazepines containing five membered rings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A. M. Monforte, G. Romeo and M. Zappala, Heterocycles, 36, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine is described. ##STR152##

The preparation of 5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepin-5-ones from 1,2-dihydro-3H-4-dimethylamino-1,5-benzodiazepin-2-ones has been described by M. DiBroccio, G. Roma, G. Grossi, M. Ghia, and F. Mattioli Eur. J. Med. Chem; 26, 489(1991). Reduction of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-ones with diborane or lithium hydride gives the tricyclic 5,6-dihydro derivatives. ##STR153##

The compounds of this invention and their preparation can be understood further by the following examples, but should not constitute a limitation thereof.

EXAMPLE 1 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,3-difluorobenzamide

To a stirred solution of 0.350 g of 2,3-difluorobenzoyl chloride in 5 ml of methylene chloride is added 0.346 ml of triethylamine. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours. The reaction mixture is filtered and the solid washed with methylene chloride. The solid is saved. The combined filtrate is washed with water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give 100 mg of a solid. The two solids are combined and dried to afford 790 mg of the desired product as a solid, m.p. 252-258° C.

EXAMPLE 2 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methoxybenzamide

To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered through hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by crystallization from ethyl acetate to give 0.430 g of the desired product as a crystalline solid, m.p. 185-188° C.

EXAMPLE 3 2-Methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzamide

To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml of triethylamine. After stirring for 3 minutes, a mixture of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO and brine. The solution is dried with Na₂ SO₄ and the volatiles concentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of the residue is purified by thick layer chromatography using 10% ethyl acetate-methylene chloride to give 160 mg of the desired product. The remainder of the crude material is purified by flash chromatography using 10% ethyl acetate in methylene chloride to give the desired product as a residue which is crystallized from ethyl acetate to give 800 mg of the desired product as white crystals, m.p. 212-215 ° C.

EXAMPLE 4 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,5-dichlorobenzamide

To a solution of 414.5 mg of 2,5-dichlorobenzoyl chloride in 5 ml of methylene chloride is added 276 μl of triethylamine. After stirring at 0° C. for 3 minutes 400 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 3 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in ethyl acetate and washed with water, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂ SO₄ and concentrated in vacuo to a residue which is purified by thick layer chromatography by elution with 1:1 ethyl acetate-hexanes to give a residue. The residue is crystallized from ethyl acetate to give 220 mg of the desired product as white crystals, m.p. 218-220° C.

EXAMPLE 5 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-methyl-2-thiophenecarboxamide

To a solution of 318 mg of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 800 mg of solid. The solid is dissolved in methylene chloride washed with water, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is filtered through hydrous magnesium silicate, dried with Na₂ SO₄ and concentrated in vacuo to give a residue which crystallizes from ethyl acetate to afford 400 mg of the desired product as a white solid, m.p. 232-235° C.

EXAMPLE 6 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide

To a solution of 415 mg of 2,4-dichlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in ethyl acetate, washed with water, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂ SO₄, filtered and concentrated in vacuo to give a residue which is crystallized from ethyl acetate to give 420 mg of the desired product as a crystalline solid, m.p., 210-212° C.

EXAMPLE 7 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H-ylcarbonyl)phenyl]-2-chlorobenzamide

To a solution of 347 mg of 2-chlorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂ SO₄, filtered and concentrated in vacuo to give a residue which is crystallized from methylene chloride to give 525 mg of the desired product as a white crystalline solid, m.p. 228-230° C.

EXAMPLE 8 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-fluorobenzamide

To a solution of 314 mg of 2-fluorobenzoyl chloride in 5 ml of methylene chloride at 0° C. is added 346 μl of triethylamine. After stirring for 3 minutes, 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 18 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in methylene chloride, washed with water, 2N citric acid, 1M NaHCO₃ and brine. The organic layer is dried with Na₂ SO₄, filtered and concentrated in vacuo to give 620 mg of the desired product as a crystalline solid, m.p. 257-260° C.

EXAMPLE 9 2-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A mixture of 0.273 g of 2-chlorophenylacetic acid is stirred at room temperature for 2 hours. The volatiles are evaporated in vacuo to a residue which is distilled with toluene several times. The residue is dissolved in 10 ml of methylene chloride containing 0.26 ml of triethylamine and while stirring 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine added. The reaction mixture is stirred at room temperature for 18 hours. The volatiles are removed and the residue dissolved in ethyl acetate which is washed with water, 1N HCl, 1M NaHCO₃ and brine. The organic layer is dried and evaporated to a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give the desired product as a yellow solid, m.p. 99-103° C.

EXAMPLE 10 1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

To a solution of 3.76 g of 1-(2-nitrophenyl)pyrrole in 20 ml of N,N-dimethylformamide at 0° C. is added dropwise with stirring 3 ml of phosphorus oxychloride. Stirring is continued for 30 minutes and the reaction mixture is heated at 90° C. for 1 hour. After cooling to room temperature the mixture is treated with crushed ice and the pH adjusted to 12 with 2N sodium hydroxide. The resulting suspension is filtered, washed with water and dried to give 5.81 g of the desired product as a light yellow solid m.p. 119-122° C.

EXAMPLE 11 4,5-Dihydro-pyrrolo-[1,2-a]-quinoxaline

To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in ether and treated with hexanes to give 0.35 g of the desired product as a beige solid m.p. 108-110° C.

EXAMPLE 12 4-[(2-Methylbenzoyl)amino]benzoic acid

A mixture of 43.42 g of ethyl 4-aminobenzoate and 40.8 g of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g of triethylamine is added dropwise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into water and the organic layer separated. The organic layer is washed with water, 1N HCl, 1M NaHCO₃ and dried over Na₂ SO₄. The solvent is removed and the solid slurried with ethyl acetate and filtered to give 57 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate as crystals, m.p. 110-115° C. A mixture of 50.7 g of the preceding compound in 280 ml of ethyl alcohol and 55 ml of 10N NaOH is refluxed for 5 minutes. The mixture is cooled to room temperature, diluted with 200 ml of water and acidified with concentrated hydrochloric acid (pH 1-2). The mixture is filtered and the solid washed with water and dried to give 51 g of the desired product as white crystals, m.p. 270-275° C.

EXAMPLE 13 4-[(2-Methylbenzoyl)amino]benzoyl chloride

A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino]benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated in vacuo. Toluene is added and the solvent removed in vacuo. Toluene is added and the mixture chilled and filtered to give the desired product as a yellow solid, 135-141° C.

EXAMPLE 14 2-Methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)ylcarbonyl)phenyl]benzamide

A mixture of 0.51 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 0.36 g of 1,1'-carbonyldiimidazole in 6 ml of tetrahydrofuran is stirred at room temperature for 1 hour. To the reaction mixture is added 0.17 g of 4,5-dihydropyrrolo-[1,2-a]-quinoxaline followed by heating at reflux for 60 hours. The volatiles are concentrated in vacuo to a residue which is dissolved in ethyl acetate. The organic layer is washed with 1N HCl, 1M NaHCO₃, brine, dried with Na₂ SO₄ and filtered through hydrous magnesium silicate. The volatiles are concentrated in vacuo to a residue which is chromatographed by elution with 1:2 ethyl acetate-hexanes to give 0.14 g of the desired product as a white solid, m.p. 206-207° C.; MASS SPEC (CI) 408(MH⁺).

                  TABLE I                                                          ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 14 with the                                          appropriately substituted aroyl chloride                                       Example                                                                        No.          Compound                                                          ______________________________________                                         15           N-[4-(pyrrolo[1,2-a]quinoxalin-                                   5(4H)-ylcarbonyl)phenyl]-2-                                                                 chlorobenzamide                                                   16           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,5-dichloro-                                               benzamide                                                         17           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dichloro-                                               benzamide, m.p. 200°-202° C.                        18           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-chloro-4-methyl-                                          benzamide                                                         19           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-4-chloro-                                          benzamide                                                         20           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dimethyl-                                               benzamide                                                         21           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,3-dimethyl-                                               benzamide, m.p. 216°-220° C.                        22           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methoxy-                                                  benzamide                                                         23           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-trifluoro-                                                methoxybenzamide                                                  24           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dimethoxy-                                              benzamide                                                         25           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dimethoxy-                                              benzamide                                                         26           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]benzamide                                       27           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dichloro-                                               benzamide                                                         28           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dimethyl-                                               benzamide                                                         29           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-(methylthio)-                                             benzamide                                                         30           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 thiophenecarboxamide                                              31           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-3-methyl-2-                                                 thiophenecarboxamide                                              32           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 furanecarboxamide                                                 33           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-3-methyl-2-                                                 furanecarboxamide                                                 34           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]benzeneacetamide                                35           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-chlorobenzene-                                            acetamide                                                         36           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methylbenzene-                                            acetamide (yellow foam); Anal. Calc'd                                          for C.sub.27 H.sub.23 N.sub.3 O.sub.2 : C, 76.9; H,5.5; N,                     10.0; Found: C, 75.6; H,6.0; N,9.4                                37           N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 thiopheneacetamide                                                ______________________________________                                    

EXAMPLE 38 N-(2-Nitrobenzoyl)pyrrole-2-carboxaldehyde

To an ice bath cooled solution of 5.6 g of 2-pyrrolecarboxaldehyde in 40 ml of tetrahydrofuran is added 2.4 g of 60% sodium hydride in mineral oil. The temperature elevates to 40° C. After stirring for 20 minutes a solution of 11.0 g of 2-nitrobenzoyl chloride in 20 ml of tetrahydrofuran is added dropwise over 20 minutes. After stirring in the cold for 45 minutes, the reaction mixture is poured into ice water and ether then filtered. The cake is washed with additional ether. The two phase filtrate is separate and the ether layer dried and concentrated in vacuo to give 10 g of a residue as a dark syrup which is scratched with ethanol to give crystals which are collected by filtration, washed with ether and then dried to afford 3.2 g of solid, m.p. 95-99° C.

EXAMPLE 39 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one

A mixture of 1.5 g of N-(2-nitrobenzoyl)pyrrole-2-carboxaldehyde in 50 ml of ethyl acetate, 2 drops of concentrated HCl and 0.3 g of 10% Pd/C is shaken in a Parr apparatus under hydrogen pressure for 1.75 hours. The mixture is filtered, 0.4 g of 10% Pd/C added and the mixture shaken in a Parr apparatus under hydrogen pressure for 2 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 1.0 g of a yellow oil. The residue is purified on thick layer chromatography plates by elution with 4:1 ethyl acetate:hexane to give 107 mg of the desired product as an oily solid.

EXAMPLE 40 2-Methyl-N-[4-[(5-oxo-5H-pyrrolo[2,1-cl][1,4]benzodiazepin-10(11H)-yl)carbonyl]phenyl]benzamide

To a stirred solution of 107 mg of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 3 ml of methylene chloride containing 0.084 ml of triethylamine is added 165 mg of 4-[(2-methylbenzoyl)amino]benzoyl chloride and stirring continued for 6 hours. The volatiles are removed in vacuo to a residue which is purified on thick layer chromatography plates with 7:3 hexane-ethyl acetate to afford the desired product as a foam.

EXAMPLE 41 N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)ylcarbonyl)phenyl]-2-methylbenzamide

To an ice-water cooled suspension of 211 mg of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 67 mg of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give a foam which is crystallized from ethyl acetate-hexane to give 157 mg of the desired product as an orange-pink solid, m.p. 185-187° C.

EXAMPLE 42 2-Methyl-N-[4-(1-chloropyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)phenyl]benzamide

To an ice-water cooled suspension of 5 mmol of 2-methyl-N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)ylcarbonyl)-phenyl]benzamide in 5 ml of tetrahydrofuran is added 5.5 mmol of N-chlorosuccinimide followed by continued stirring in the cold for 10 minutes. The bath is removed and stirring continued for 2.25 hours. The reaction mixture is added to ice-water and extracted with ether. The organic layer is dried and concentrated in vacuo to give the desired product as a solid.

                  TABLE II                                                         ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 42.                                                  Example                                                                        No.            Compound                                                        ______________________________________                                         43             2-chloro-N-[4-(1-chloropyrrolo-                                                [1,2-a]quinoxalin-                                                             5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       44             2,4-dichloro-N-[4-(1-chloro-                                                   pyrrolo-[1,2-a]quinoxalin-                                                     5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       45             2,5-dichloro-N-[4-(1-chloro-                                                   pyrrolo-[1,2-a]quinoxalin-                                                     5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       46             2,3-dimethyl-N-[4-(1-chloro-                                                   pyrrolo-[1,2-a]quinoxalin-                                                     5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       47             2,4-dimethyl-N-[4-(1-chloro-                                                   pyrrolo-[1,2-a]quinoxalin-                                                     5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       48             2,5-dimethyl-N-[4-(1-chloro-                                                   pyrrolo-[1,2-a]quinoxalin-                                                     5(4H)-ylcarbonyl)phenyl]-                                                      benzamide                                                       ______________________________________                                    

EXAMPLE 49 3-Chloro-10,11-dihydro-10-(4-nitrobenzoyl-5H-pyrrolo[2,1-c][1,4]-benzodiazepine

To an ice-water cooled solution of 250 mg of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 6 ml of tetrahydrofuran is added 100 mg of N-chlorosuccinimide. The reaction mixture is stirred in the cold for 30 minutes and at room temperature for 2 hours. The reaction mixture is poured into ice water, stirred for 5 minutes and extracted with ether. The organic layer is dried and concentrated in vacuo to give 0.2 g of a yellow foam. Trituration with ethyl alcohol gives 66 mg of the desired product as a yellow solid, m.p. 119-125° C.

EXAMPLE 50 3-Chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-nitroaminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2.5 mmol of anhydrous hydrazine, 50 mg of palladium on carbon and 10 ml of ethyl alcohol is refluxed for 1.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness to give the desired product as a solid.

EXAMPLE 51 N-[4-(3-Chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-methylbenzamide

A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 2 mmol of triethylamine, and 1.1 mmol of 2-methylbenzoylchloride in 8 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with water, and 1M NaHCO₃ and dried (Na₂ SO₄). The solvent is removed in vacuo to give a solid which is recrystallized from dichloromethane-hexane to give crystals, 185-187° C.

                  TABLE III                                                        ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 51 with the                                          appropriately substituted aroyl chloride                                       Example                                                                        No.           Compound                                                         ______________________________________                                         52            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-chlorobenzamide                               53            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,5-dichloro-                                                 benzamide                                                        54            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,4-dichloro-                                                 benzamide (solid foam), Anal.                                                  Calc'd for C.sub.26 H.sub.18 C.sub.3 N.sub.3 O.sub.2 :                         C,61.1;                                                                        H,3.6; N,8.2; Cl, 20.8; Found:                                                 C,60.0; H,3.5; N,7.7; Cl, 20.3                                   55            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-fluoro-                                                     benzamide                                                        56            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-chloro-4-                                                   methylbenzamide                                                  57            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methyl-4-                                                   chlorobenzamide                                                  58            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,4-dimethyl-                                                 benzamide                                                        59            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,3-dimethyl-                                                 benzamide                                                        60            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methoxy-                                                    benzamide                                                        61            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-trifluoro-                                                  methoxybenzamide                                                 62            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,4-dimethoxy-                                                benzamide                                                        63            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,6-dimethoxy-                                                benzamide                                                        64            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]benzamide                                        65            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,6-dichloro-                                                 benzamide                                                        66            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2,6-dimethyl-                                                 benzamide                                                        67            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methylthio-                                                 benzamide                                                        68            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methyl-3-                                                   thiophenecarboxamide                                             69            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-3-methyl-2-                                                   thiophenecarboxamide                                             70            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methyl-3-                                                   furanecarboxamide                                                71            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-3-methyl-2-                                                   furanecarboxamide                                                72            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]phenylacetamide                                  73            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-chlorophenyl-                                               acetamide                                                        74            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methylbenzene-                                              acetamide                                                        75            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methyl-3-                                                   thiopheneacetamide                                               76            N-[4-(3-Chloro-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepin-10(11H)yl-                                                  carbonyl)phenyl]-2-methyl-3-                                                   furanacetamide                                                   ______________________________________                                    

EXAMPLE 77 1-(2-Nitrobenzyl)-2-pyrrolecarboxaldehyde

To 5.56 g of 60% sodium hydride in mineral oil, washed three times with hexane, is added 300 ml of N,N-dimethylformamide under argon. The reaction mixture is cooled in an ice-bath and 13.2 g of pyrrole-2-carboxaldehyde is added slowly. The reaction mixture becomes a complete solution and is stirred for an additional 10 minutes. While stirring, 30.0 g of 2-nitrobenzyl bromide is added slowly. After complete addition, the reaction mixture is stirred for 30 minutes, the ice bath is removed and the reaction mixture stirred at room temperature for 24 hours. The N,N-dimethylformamide is concentrated in vacuo to give a residue which is stirred with ice water for 1 hour. The resulting solid is collected, air dried, then vacuum dried to give 30.64 g of the desired product as a tan solid, m.p. 128-132° C.

EXAMPLE 78 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 30.6 g of 1-(2-nitrobenzyl)-2-pyrrolecarboxaldehyde and 3.06 g of 10% Pd/C in 400 ml of ethyl acetate and 400 ml of ethyl alcohol is hydrogenated over 18 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is treated with activated carbon and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is dissolved in methylene chloride containing ethyl alcohol. The solution is passed through a pad of silica gel and the pad washed with a 7:1 hexane-ethyl acetate solution to give 16.31 g of the desired product as solid, m.p. 145-148 ° C.

EXAMPLE 79 10,11-Dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 3.3 g of 10,11-dihydro-5H-yrrolo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 5.0 ml of triethylamine followed by ice bath cooling. A solution of 4.0 g of 4-nitrobenzoyl chloride in 20 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO₃, brine, dried with Na₂ SO₄ and filtered. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with ethyl acetate. The combined filtrate is concentrated in vacuo to give 5.3 g of the desired product as a yellow solid, m.p. 188-190° C.

EXAMPLE 80 10,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 2.00 g of 10,11-dihydro-10(4-itrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 15 ml of ethyl alcohol and 15 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride, passed through silica gel and the pad washed with 3:1 ethyl acetate-hexane. The filtrate is concentrated in vacuo to give 1.5 g of the desired product as a yellow solid, m.p. 166-168° C.

EXAMPLE 81 10,11-Dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 21.58 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 325 ml of ethyl alcohol is added 2.15 g of 10% Pd/C and 5.16 g of hydrazine followed by stirring and heating under reflux for 15 hours. The room temperature reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 19.2 g of the desired product as a tan solid. The solid is purified by flash chromatography using 7:1 ethyl acetate-hexane to give 17.97 g of the desired product, m.p. 166-168° C.

EXAMPLE 82 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-chlorobenzo[b]thiophene-2-carboxamide

To a stirred solution of 0.440 g of 3-chlorobenzo[b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is washed with water, 1N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220-222° C.

EXAMPLE 83 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2,3-dimethylbenzamide

To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4- aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168-170° C.

EXAMPLE 84 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-ethoxybenzamide

To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.890 g of solid which is crystallized from ethyl acetate to give 0.540 g of the desired product as a white solid, m.p. 160-176° C.

EXAMPLE 85 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-(methylthio)benzamide

To a stirred solution of 0.364 g of 2-(methylthio )benzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl alcohol to give 0.480 g of the desired product as a white solid, m.p. 171-174° C.

EXAMPLE 86 3-Methylbenzo[b]thiophene-2-acetyl chloride

A mixture of 2.0 g of 3-methylbenzo[b]thiophene-2-acetic acid and 19.4 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.25 g of the desired product as a residue.

EXAMPLE 87 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-3-methylbenzo[b]thiophene-2-acetamide

To a stirred solution of 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. An additional 0.445 g of 3-methylbenzo[b]thiophene-2-acetyl chloride, 0.346 g of triethylamine and 30 mg of dimethylaminopyridine is added and stirring continued for an additional 18 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.320 g of the desired product as a yellow foam.

EXAMPLE 88 4-Chloro-2-methoxybenzoyl chloride

A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is is concentrated from toluene three times and dried under vacuum to give 2.0 g of the desired product as a residue.

EXAMPLE 89 N-[4-(5H-Pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)ylcarbonyl)phenyl]-4-chloro-2-methoxybenzamide

To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.320 g of the desired product as a white crystals, m.p. 222-224° C.

EXAMPLE 90 2-(Trifluoromethyl)benzoyl chloride

A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a residue.

EXAMPLE 91 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide

To a stirred solution of 0.413 g of 2-trifluoromethylbenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted with 50 ml of ethyl acetate and washed with water, 2N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is crystallized from ethyl acetate to afford 0.5 g of a solid which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give a solid which is crystallized from ethyl acetate to afford 0.210 g of the desired product as a white crystals, m.p. 226-228° C.

EXAMPLE 92 2-Methylphenylacetyl chloride

A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil.

EXAMPLE 93 N-[4(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzeneacetamide

To a stirred solution of 0.334 g of 2-methylphenylacetyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.385 g of the desired product as white crystals, m.p. 198-200° C.

EXAMPLE 94 10,11-Dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4[benzodiazepine

A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 g of thionyl chloride in 75 ml of chloroform is heated at reflux under argon for 48 hours. The volatiles are removed in vacuo to a residue which is evaporated with toluene several times in vacuo. The residue is partially dissolved in methylene chloride and filtered free of solids and the filtrate evaporated in vacuo to give 1.47 g of the desired acid chloride. A 1.36 g sample of the acid chloride, 0.90 g of N,N-diisopropylethylamine and 1.25 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is allowed to stand at room temperature for 8 hours. Water is added to the reaction mixture, the organic layer is separated and dried over Na₂ SO₄, filtered and hexane added to the filtrate at the boil to give 1.4 g of the desired product as crystals, m.p. 246-248° C.

EXAMPLE 95 10,11-Dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4 ]benzodiazepine

A mixture of 1.22 g 10,11-dihydro-10-(3-methyl-4-nitro-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.2 g of 10% Pd/C and 0.35 g of anhydrous hydrazine in 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour. The reaction mixture is filtered hot through diatomaceous earth and evaporated in vacuo to a residue. The residue is crystallized from methylene chloride-hexane to give 0.95 g of the desired product as crystals, m.p. 232-234° C.

EXAMPLE 96 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)ylcarbonyl)-2-methylphenyl]-2-methylbenzamide

A solution of 0.83 g of 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.5 g of N,N-diisopropylethylamine and 0.6 g of 2-methylbenzoyl chloride in 50 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, the organic layer dried with Na₂ SO₄ and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.75 g of a solid which is crystallized from methylene chloride-hexane to give 0.61 g of the desired product, m.p. 125-130° C.

                  TABLE IV                                                         ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 96 with the                                          appropriately substituted aroyl chloride                                       Example                                                                        No.             Compound                                                       ______________________________________                                         97              N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-2-                                                   chlorobenzamide                                                98              N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-2,-                                                  5-dichlorobenzamide                                            99              N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2,4-dichlorobenzamide, m.p.                                                    213°-215° C.                                     100             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-chloro-4-methylbenzamide                                     101             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methyl-4-chlorobenzamide                                     102             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2,3-dimethylbenzamide                                          103             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-2-                                                   methoxybenzamide                                               104             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-2-                                                   trifluoromethoxybenzamide                                      105             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-2,-                                                  4-dimethoxybenzamide                                           106             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     benzamide                                                      107             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methylthiobenzamide                                          108             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2,6-dichlorobenzamide                                          109             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methyl-3-thiophenecarbox-                                                    amide                                                          110             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methyl-3-thiophene-                                                          carboxamide                                                    111             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methyl-3-furancarboxamide                                    112             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     3-methyl-2-furancarboxamide                                    113             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     phenylacetamide                                                114             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-chlorophenylacetamide                                        115             N-[4-(5H-pyrrolo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-yl-                                                      carbonyl)-2-methylphenyl]-                                                     2-methylphenylacetamide                                        ______________________________________                                    

EXAMPLE 116 10,11-Dihydro-10-[4-[[[(2-methylphenyl]amino]-carbonyl]amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.93 g 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiezepine and 0.37 g of o-tolyl isocyanate in 50 ml of tetrahydrofuran is heated at reflux under argon for 24 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.68 g of the desired product as crystals, m.p. 155-158° C.

EXAMPLE 117 N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-1H-indole-5-carboxamide

To a solution of 319 mg of indole-5-carboxylic acid in 5 ml of tetrahydrofuran is added 418.4 mg of 1,1'-carbonyldiimidazole under argon with icebath cooling. The cooling bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in 3 ml of xylene followed by 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and heating at 120° C. for 18 hours. The volatiles are evaporated in vacuo to a residue which is partitioned between 40 ml of ethyl acetate and water. The organic layer is dried over Na₂ SO₄ and the volatiles evaporated in vacuo to a residue which is purified by chromatography on preparative plates by elution with 1:1 ethyl acetate-hexane to give 140 mg of the desired product as an orange solid, m.p. 130-170° C.

EXAMPLE 118 1-(o-Nitrobenzyl)-imidazole-2-carboxaldehyde

A 2.0 g portion of sodium hydride (60% in oil) is washed with pentane two times. To the residue is added 110 ml of N,N-dimethylformamide under argon. With stirring and external cooling, 4.80 g of 2-imidazolecarboxaldehyde is added and the cooling bath removed. Slight external heating results in a yellow solution. The reaction mixture is chilled in ice and 10.8 g of 2-nitrobenzyl bromide is added. The reaction mixture is stirred at 0° C. for 18 hours. The volatiles are removed in vacuo to a residue which is stirred with ice water, filtered and the cake washed well with water and suction dried to give 10.9 g of the desired product as a solid, m.p. 141-144° C. MH+ 232.

EXAMPLE 119 10,11-Dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine

A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole-2-carboxaldehyde is dissolved in 150 ml of hot ethyl alcohol, cooled to room temperature and filtered. To the filtrate is added 0.5 g of 10% Pd/C and the mixture hydrogenated at 48 psi for 4 hours. An additional 0.5 g of 10% Pd/C is added and hydrogenation continued for 25 hours at 65 psi. The mixture is filtered through diatomaceous earth and the cake washed with ethyl acetate. The filtrate is evaporated in vacuo to a residue which is dissolved in methylene chloride, treated with activated carbon, filtered through diatomaceous earth and hexanes added to the filtrate at the boil to give 1.86 g of the desired product as a crystalline solid, m.p. 164-170° C.

EXAMPLE 120 10,11-Dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine

To a suspension of 4 mol of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran is added a 1 mol solution of 10,11-dihydro-11-oxo-5H-imidazo-[2,1-c][1,4]benzodiazepine and the mixture is refluxed for 24 hours and cooled at 0° C. To the mixture is added dropwise 0.12 ml of water and 6 ml of 1N sodium hydroxide. The mixture is extracted with ethyl acetate and the solvent removed to give the desired product as a solid. Recrystallization from methylene chloride-hexane gives crystals, m.p. 164-170° C.

EXAMPLE 121 N-[4-(5H-imidazo[2,1-c][1,4]benzodiazelin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. After stirring for 3 minutes, 5 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 1 hour and the volatiles are concentrated in vacuo. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, and brine. The solution is dried with Na₂ SO₄ and the volatiles concentrated in vacuo to give the desired product as a solid.

EXAMPLE 122 10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

To a solution of 10 mmol of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 10 mol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, and brine. The organic layer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give desired product as a solid.

EXAMPLE 123 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

A mixture of 5 mmol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours in a Parr hydrogenator at 35 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.

EXAMPLE 124 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine

To a solution of 5 mol of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 100 ml of ethyl alcohol is added 0.5 g of 10% Pd/C and 10 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography to give the desired product as a solid.

EXAMPLE 125 N-[4-(5H-Imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 1 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. After stirring for 15 minutes, 1 mmol of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid.

                  TABLE V                                                          ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 125 with the                                         appropriately substituted aroyl chloride                                       Example                                                                        No.             Compound                                                       ______________________________________                                         126             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-                                                          chlorobenzamide                                                127             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,5-                                                        dichlorobenzamide                                              128             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,4-                                                        dichlorobenzamide                                              129             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-                                                          fluorobenzamide                                                130             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-chloro-                                                   4-methylbenzamide                                              131             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-methyl-                                                   4-chlorobenzamide                                              132             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,4-                                                        dimethylbenzamide                                              133             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,3-                                                        dimethylbenzamide                                              134             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-                                                          methoxybenzamide                                               135             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2-                                                          trifluoromethoxybenzamide                                      136             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         4-dimethoxybenzamide                                           137             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         6-dimethoxybenzamide                                           138             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            benzamide                                                      139             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         6-dichlorobenzamide                                            140             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         6-dimethylbenzamide                                            141             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         methylthiobenzamide                                            142             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         methyl-3-thiophenecarboxamide                                  143             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-3,-                                                         methyl-2-thiophenecarboxamide                                  144             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-2,-                                                         methyl-3-furanecarboxamide                                     145             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-3,-                                                         methyl-2-furanecarboxamide                                     146             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            phenylacetamide                                                147             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            2-chlorophenylacetamide                                        148             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            2-methylphenylacetamide                                        149             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            2-methyl-3-thiopheneacetamide                                  150             N-[4-(5H-imidazo[2,1-c][1,4]-                                                  benzodiazepin-10(11H)-                                                         ylcarbonyl)phenyl]-                                                            2-methyl-3-furanacetamide                                      ______________________________________                                    

EXAMPLE 151 N-[4-(7-Chloro-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H) -ylcarbonyl]phenyl]-2-methylbenzamide

As described for Example 125 a mixture of 1 mmol of 7-chloro-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.

EXAMPLE 152 N-[4-(7-Methoxy-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]phenyl]-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of 7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred for 3 hours at room temperature and worked up to give the product as a solid.

EXAMPLE 153 N-[4-(7,8-Methylenedioxy-5H-imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl]phenyl]-2-methylbenzamide

As described for Example 125 a mixture of 1.0 mmol of 7,8-methylenedioxy-10,11-dihydro-5H-imidazo-[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.

EXAMPLE 154

4,5-Dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline

To a solution of 5 mmol of 4,5-dihydro-pyrrolo-[1,2-a]quinoxaline in 50 ml of methylene chloride under argon is added 10 mmol of triethylamine followed by ice bath cooling. A solution of 5 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1 N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product (from ethyl acetate) as a solid, m.p. 174-178° C.

EXAMPLE 155

4,5-Dihydro-5(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline

A mixture of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product, m.p. 225-228° C.

EXAMPLE 156

4,5-Dihydro-5(4-aminobenzoyl)pyrrolo[2-a]quinoxaline

To a solution of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 2 hours. The hot reaction mixture is filtered through diatomaceous earth and the filter cake washed with hot chloroform and the filtrate concentrated in vacuo. The residue is triturated with ethyl acetate and the mixture filtered to give the desired product as crystals, m.p. 225-228° C.

EXAMPLE 157

N-[4-(pyrrolo[2-a]quinoxalin-5(4H)-yl-carbonyl)penyl]-2-methylbenzamide

To a stirred solution of 1.5 mmol of 2-methyl-benzoyl chloride in 10 ml of methylene chloride is added 3 mmol of triethylamine. After stirring for 15 minutes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)-pyrrolo[1,2-a]quinoxaline is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, 1 N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid, m.p. 206-207° C.

                  TABLE VI                                                         ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 157 with the                                         appropriately substituted aroyl chloride                                       Example                                                                        No.          Compound                                                          ______________________________________                                         158          N-[4-(pyrrolo[1,2-a]quinoxalin-                                   5(4H)ylcarbonyl)phenyl]-2-                                                                  chlorobenzamide                                                   159          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl]phenyl-2,5-dichloro-                                                benzamide                                                         160          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dichloro-                                               benzamide, m.p. 200°-202° C.                        161          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-chloro-4-methyl-                                          benzamide                                                         162          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-4-chloro-                                          benzamide                                                         163          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dimethyl-                                               benzamide                                                         164          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,3-dimethyl-                                               benzamide, m.p. 216°-220° C.                        165          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methoxy-                                                  benzamide                                                         166          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-trifluoro-                                                methoxybenzamide                                                  167          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,4-dimethoxy-                                              benzamide                                                         168          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dimethoxy-                                              benzamide                                                         169          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]benzamide                                       170          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dichloro-                                               benzamide                                                         171          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2,6-dimethyl-                                               benzamide                                                         172          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-(methylthio)-                                             benzamide                                                         173          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 thiophenecarboxamide                                              174          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-3-methyl-2-                                                 thiophenecarboxamide                                              175          4-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 furanecarboxamide                                                 176          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-3-methyl-2-                                                 furanecarboxamide                                                 177          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]benzeneacetamide                                178          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-chlorobenzene                                             acetamide                                                         179          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methylbenzene                                             acetamide, yellow foam                                            180          N-[4-(pyrrolo[1,2-a]quinoxalin-5(4H)-                                          ylcarbonyl)phenyl]-2-methyl-3-                                                 thiopheneacetamide                                                ______________________________________                                    

EXAMPLE 181

9,10-Dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine

To a suspension of 4 mmol of lithium aluminum hydride in 25 ml of anhydrous tetrahydrofuran is added 1 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a]-[1,4]diazepin-9-one. The mixture is refluxed for 12 hours and allowed to stand overnight. To the mixture is added dropwise 0.12 ml of water and then 6 ml of 1N sodium hydroxide. The mixture is extracted with ethyl acetate and the extract dried(Na₂ SO₄). The volatiles are removed in vacuo to give the desired product as a solid.

EXAMPLE 182

9,10-Dihydro-4H-furor[2,3-e]pyrrolo[2-a][1,4]diazepine

A solution of 1 mmol of 4H-furo[2,3-e]-pyrrolo[1,2-a][1,4]diazepine and 0.2 g of 10% Pd/C in 10 ml of 10 ml of ethanol is hydrogenated for 18 hours.

The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated in vacuo to give the desired product as a solid.

EXAMPLE 183

N-[4-(4H-Furor[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.1 mmol of 4-[(2-methyl-benzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to 0° C. is added 1.5 mmol of triethylamine. To the mixture is added 1 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine and the mixture stirred at toom temperature for 2 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO₃ and brine. The solution is dried with Na₂ SO₄ and the volatiles concentrated in vacuo to give a solid which is purified by flash chromatography to give the desired product.

EXAMPLE 184

9,10-Dihydro-10-(4-nitrobenzoyl)-4H-furor[2,3-e]pyrrolo[2-a[4,1diazepine

To a solution of 1.0 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of methylene chloride under argon is added 1.5 mmol of triethylamine followed by ice bath cooling. A solution of 1.1 mmol of 4-nitrobenzoyl chloride in 5 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture is stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1N HCl, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.

EXAMPLE 185

9,10-Dihydro-10-(4-aminobenzoyl)-4H-furor[2,3-e]pyrrolo[1,2-a][1,4diazepine

A mixture of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepine in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.

EXAMPLE 186

9,10-Dihydro-10-(4-aminobenzoyl)-4H-furor[2 3-e]pyrrolo[1,2-a][1,4]diazepine

To a solution of 1 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]-diazepine in 20 ml of ethyl alcohol is added 0.2 g of 10% Pd/C and 2.5 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The room temperature reaction mixture is filtered through diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.

EXAMPLE 187

N-[4-(4H-Furor[2,3]-pyrrolo[1,2-a[1,4-diazepin-10(9H)-ylcarbonyl)phenyl]-2-methyl benzamide

To a stirred solution of 1.1 mmol of 2-methyl-benzoyl chloride in 10 ml of methylene chloride is added 1.5 mmol of triethylamine. To the mixture is added 1.1 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-furo-[2,3-e]pyrrolo(1,2-a][1,4]diazepine and the mixture is stirred for 5 hours. The reaction mixture is washed with water, 1N citric acid, NAHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄ filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a solid.

                  TABLE VII                                                        ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 187 with the                                         appropriately substituted aroyl chloride                                       Example                                                                        No.           Compound                                                         ______________________________________                                         188           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-chlorobenzamide                                        189           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,5-dichlorobenzamide                                    190           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,4-dichlorobenzamide                                    191           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-chloro-4-methylbenzamide                               192           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methyl-4-chlorobenzamide                               193           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,4-dimethylbenzamide                                    194           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,3-dimethylbenzamide                                    195           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methoxybenzamide                                       196           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-trifluoromethoxybenzamide                              197           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,4-dimethoxybenzamide                                   198           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methoxy-4-chlorobenzamide                              199           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2,6-dichlorobenzamide                                    200           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methylthiobenzamide                                    201           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methyl-3-thiophene-                                                  carboxamide                                                      202           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-3-methyl-2-thiophene-                                                  carboxamide                                                      203           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methyl-3-furane-                                                     carboxamide                                                      204           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-3-methyl-2-furane-                                                     carboxamide                                                      205           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-chlorobenzeneacetamide                                 206           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methylbenzeneacetamide                                 207           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-2-methyl-3-thiophene-                                                  acetamide                                                        208           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-cyclohexanecarboxamide                                   209           N-[4-(4H-Furo[2,3-e]pyrrolo[1,2-a]-                                            [1,4]diazepin-10(9H)-ylcarbonyl)-                                              phenyl]-cyclohexylacetamide                                      ______________________________________                                    

EXAMPLE 210

N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g of 4-[(2-methyl-benzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.5 ml of triethylamine. To the mixture is added 5 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO₃ and brine. The solution is dried with Na2SO4 and the solvent removed in vacuo. The residue is purified by flash chromatography on silica gel with ethyl acetate-hexane to give the desired product, m.p. 142°-146° C.

EXAMPLE 211

5,10-Dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c]-[1,4benzodiazepine

To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄ filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid, m.p. 227°-229° C.

EXAMPLE 212

5,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c]-[1,4benzodiazepine

A mixture of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product as a tan solid.

EXAMPLE 213

5,10-Dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c]-[1,4benzodiazepine

To a solution of 5 mmol of 5,10-dihydro-5-(4-nitrobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is heated under reflux for 3 hours, and the mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid, exact mass by mass spectrometry: 305.1402(M+H).

EXAMPLE 214

N-[4-(4H-Pyrazolo[5,1-c][1,4benzodiazepin-5(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methyl-benzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then washed with water, NaHCO₃, and brine. The organic layer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. ₁₄₂°-146° C.

                  TABLE VIII                                                       ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 214 with the                                         appropriately substituted aroyl chloride                                       Example                                                                        No.           Compound                                                         ______________________________________                                         215           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methoxybenzeneacetamide, m.p.                                                185-188° C.                                               216           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,5-dichlorobenzamide                                            217           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,4-dichlorobenzamide, colorless                                               foam; exact mass by mass spectro-                                              metry: 479.0896(M + H)                                           218           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-chloro-4-methylbenzamide                                       219           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methyl-4-chlorobenzamide                                       220           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,4-dimethylbenzamide                                            221           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,3-dimethylbenzamide                                            222           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methoxybenzamide                                               223           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-trifluoromethoxybenzamide                                      224           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,4-dimethoxybenzamide                                           225           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,6-dimethoxybenzamide                                           226           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            benzamide                                                        227           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,6-dichlorobenzamide                                            228           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2,6-dimethylbenzamide                                            229           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methylthiobenzamide                                            230           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methyl-3-thiophenecarboxamide                                  231           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            3-methyl-2-thiophenecarboxamide                                  232           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methyl-3-furanecarboxamide                                     233           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            3-methyl-2-furanecarboxamide                                     234           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            3-cyclohexenecarboxamide                                         235           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-chlorobenzeneacetamide                                         236           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methylbenzeneacetamide                                         237           N-[4-(4H-Pyrazolo[5,1-c][1,4]benzo-                                            diazepin-5(10H)-ylcarbonyl)phenyl]-                                            2-methyl-3-thiopheneacetamide                                    ______________________________________                                    

EXAMPLE 238

9,10-Dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine

To a mixture of 7.0 g of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2 N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2 N citric acid, water and dried (Na₂ SO₄). The solvent is removed in vacuo to give the desired product as a solid.

EXAMPLE 239

N-[4-(4H-Pyrazolo[2-a]thieno[2,3-a][1,4]-diazepin-10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to ₀° C. is added 1.5 ml of triethylamine. To the mixture is added 5 mmol of 9,10-dihydro-4H-pyrazolo[1,2-a]thieno[2,3-e][1,4]diazepine. The cooling bath is removed and the reaction mixture is allowed to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2 N citric acid, aqueous NAHCO₃ and brine. The solution is dried with Na₂ SO₄ and the solvent removed in vacuo to give a solid. The solid is purified by flash chromatography on silica gel to give the desired product.

EXAMPLE 240

9,10-Dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thienor[2,3-e][1,4diazepine

To a solution of 10 mmol of 9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e](1,4]diazepine in 50 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 1 N HCl, NAHCO₃, and brine. The organic layer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.

EXAMPLE 241

9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4diazepine

A mixture of 2 g of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]-diazepine in 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product.

EXAMPLE 242

9,10-Dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[2-a]thieno[2,3-e][1,4diazepine

To a solution of 5 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno(2,3-e][1,4]-diazepine in 25 ml of ethyl alcohol is added 0.13 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.

EXAMPLE 243

N-[4-(4H-Pyrrolo[2-a]thieno[2,3-e][1,4diazepin-10(9H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 5 mmol of 2-methyl-benzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 9,10-dihydro-10-(4-aminobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e]-[1,4]diazepine and the mixture stirred for 5 hours. The reaction mixture is washed with water, 2 N citric acid, NaHCO₃, and brine. The organic layer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.

                  TABLE IX                                                         ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 243 with the                                         appropriately substituted aroyl chloride.                                      Example                                                                        No.            Compound                                                        ______________________________________                                         244            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-chloro-                                                     benzamide                                                       245            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,5-dichloro-                                                 benzamide                                                       246            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,4-dichloro-                                                 benzamide                                                       247            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-chloro-                                                     4-methylbenzamide                                               248            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-methyl-                                                     4-chlorobenzamide                                               249            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,4-                                                          dimethylbenzamide                                               250            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,3-                                                          dimethylbenzamide                                               251            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-methoxy-                                                    benzamide                                                       252            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            trifluoromethoxybenzamide                                       253            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl)]-2,4-                                                         dimethoxybenzamide                                              254            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dimethoxybenzamide                                              255            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dichlorobenzamide                                               256            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dimethylbenzamide                                               257            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            methoxy-4-chlorobenzamide                                       258            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            methoxybenzeneacetamide                                         259            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-(methylthio)-                                               benzamide                                                       260            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            methyl-3-thiophenecarboxamide                                   261            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-3-methyl-2-                                                   thiophenecarboxamide                                            262            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-3-methyl-2-                                                   furancarboxamide                                                263            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-3-                                                            chlorophenylacetamide                                           264            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            methylbenzeneacetamide                                          265            N-[4-(4H-pyrrolo[1,2-a]thieno-                                                 [2,3-e][1,4]diazepin-10(9H)-yl                                                 carbonyl)phenyl]-2-                                                            methyl-3-thiopheneacetamide                                     ______________________________________                                    

EXAMPLE 266

4,10-Dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4diazepine

To a suspension of 7.0 g of 5-oxo-4,5-dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 25 ml of anhydrous tetrahydrofuran is added 9 ml of 10 M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours. The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2 N NaOH. The mixture is refluxed 5 hours and filtered. The solid is extracted with dichloromethane and the extract is washed with 2 N citric acid, water and dried (Na₂ SO₄). The solvent is removed to give a solid.

EXAMPLE 267

N-[4-(5H-Pyrazolo[1,2-a]thieno[3,2-e][1,4-diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a mixture of 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 20 ml of methylene chloride, cooled to 0° C. is added 7.5 mmol of triethylamine and 5 mmol of 4,10-dihydro-5H-pyrazolo-[1,2-a]thieno[3,2-e](1,4]diazepine. The cooling bath is removed and the reaction mixture is allowed to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and the solution washed with water, 2 N citric acid, aqueous NaHCO and brine. The solution is dried with Na₂ SO₄ and the solvent concentrated in vacuo to give a solid. The solid is purified by flash chromatography on silica gel to give the desired product as a solid and foam, m.p. 162°-188° C., Anal. Calc'd for C₂₅ H₂₁ N₃ O₂ S: C,70.2; H,5.0N,9.8; S,7.5 Found: C,69.5, H,5.2 N,9.6; S,7.0.

EXAMPLE 268

4,10-Dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[2-a]thieno[3,2-e][1,4]diazepine

To a solution of 3 mmol of 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine in 10 ml of methylene chloride under argon is added 5 mmol of triethylamine followed by ice bath cooling. A solution of 3.3 mmol of 4-nitrobenzoyl chloride in 3 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 2 N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give desired product as a solid.

EXAMPLE 269

4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4diazepin

A mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]-diazepine in 25 ml of ethyl alcohol and 25 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated i vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.

EXAMPLE 270

4,10-Dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine

To a mixture of 5 mmol of 4,10-dihydro-4-(4-nitrobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e][1,4]-diazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.

EXAMPLE 271

N-[4-(5H-Pyrrolo[2-a]thieno[3,2-e][1,4]diazepin-4(10H)-ylcarbonyl)phenyl]-2-methylbenzamide

To a stirred solution of 3 mmol of 2-methyl-benzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 4,10-dihydro-4-(4-aminobenzoyl)-5H-pyrrolo-[1,2-a]thieno[3,2-e]-[1,4]diazepine. The mixture is stirred for 5 hours. The reaction mixture is washed with water, 2 N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 162°-188° C. (amorphous)

                  TABLE X                                                          ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 271 with the                                         appropriately substituted aroyl chloride.                                      Example                                                                        No.           Compound                                                         ______________________________________                                         272           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-chloro-                                                     benzamide                                                        273           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,5-dichloro-                                                 benzamide                                                        274           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,4-dichloro-                                                 benzamide (solid foam),                                                        m.p. 105-190° C.; Anal Calc'd for                                       C.sub.24 H.sub.17 N.sub.3 Cl.sub.2 O.sub.2 S: C,59.8;                          H,3.6;                                                                         N,8.7; S,6.6, Cl, 14.7 Found:                                                  C,59.6; H,3.8; N,8.1; S,5.5; Cl,14.0                             275           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-chloro-                                                     4-methylbenzamide                                                276           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methyl-                                                     4-chlorobenzamide                                                277           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,4-dimethyl-                                                 benzamide                                                        278           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,3-dimethyl-                                                 benzamide                                                        279           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methoxy-                                                    benzamide                                                        280           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-trifluoro-                                                  methoxybenzamide                                                 281           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,4-                                                          dimethoxybenzamide                                               282           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dimethoxybenzamide                                               283           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dichlorobenzamide                                                284           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2,6-                                                          dimethylbenzamide                                                285           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methylthio-                                                 benzamide                                                        286           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-                                                            methyl-3-thiophenecarboxamide                                    287           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-3-                                                            methyl-2-thiophenecarboxamide                                    288           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-3-                                                            methyl-2-furancarboxamide                                        289           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-3-chloro-                                                     benzeneacetamide                                                 290           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methoxy-                                                    benzeneacetamide                                                 291           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methoxy-4-                                                  chlorobenzamide                                                  292           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-methylbenzene-                                              acetamide                                                        293           N-[4-(5H-pyrrolo[1,2-a]thieno-                                                 [3,2-e][1,4]diazepin-4(10H)-yl                                                 carbonyl)phenyl]-2-                                                            methyl-3-thiopheneacetamide                                      ______________________________________                                    

EXAMPLE 294

6,7-Dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a]-[1,5benzodiazepine

To a solution of 10 mmol of 6,7-dihydro-5H-[1,2-a][1,5]benzodiazepine in 30 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 2 N citric acid, NaHCO₃, and brine. The reaction mixture is dried with Na₂ SO₄ filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.

EXAMPLE 295

6,7-Dihydro-5- (4-aminobenzoyl) -5H-pyrrolo[1,2-a]-[1,5]benzodiazepine

A mixture of 2.0 g of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine, 20 ml of ethyl alcohol and 20 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatqmaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography on silica gel to give the desired product.

EXAMPLE 296

6,7-Dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]-[1,5]benzodiazepine

To a solution of 5 mmol of 6,7-dihydro-5-(4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 25 ml of ethyl alcohol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.

EXAMPLE 297

N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5benzodiazepin-5-yl)carbonyl]phenyl]-2-methylbenzamide

To a mixture of 1.37 g (5 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 10 ml of methylene chloride, cooled to 0° C. is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5H-pyrrolo-[(1,2-a][1,5]benzodiazepine. The cooling bath is removed and the reaction mixture is allowed to stir at room temperature for 48 hours. The volatiles are removed in vacuo to give a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2 N citric acid, aqueous NaHCO₃ and brine. The solution is dried with Na₂ SO₄ and the solvent removed in vacuo to give a solid. The solid is triturated with ether-hexane to give the desired product, mass spectrum (CI):422(M+H).

EXAMPLE 298

N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-[1,5]benzodiazepin-5-yl)carbonyl)phenyl]-2-methyl-benzamide

To a stirred solution of 5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 7 mmol of triethylamine and 5 mmol of 6,7-dihydro-5-(4-aminobenzoyl)-5H-pyrrolo[1,2-a]-[1,5]benzodiazepine. The reaction mixture is washed with water, 2 M citric acid, NaHCO₃, and brine. The organic layer is dried with Na₂ SO₄, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid; mass spectrum (CI) :422(M+H).

                  TABLE XI                                                         ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 298 with the                                         appropriately substituted aroyl                                                chloride.                                                                      Example                                                                        No.           Compound                                                         ______________________________________                                         299           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            chlorobenzamide                                                  300           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,5-di-                                                       chlorobenzamide                                                  301           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,4-di-                                                       chlorobenzamide                                                  302           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            chloro-4-methylbenzamide                                         303           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            methyl-4-chlorobenzamide                                         304           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,4-                                                          dimethylbenzamide                                                305           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,3-                                                          dimethylbenzamide                                                306           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            methoxybenzamide                                                 307           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            trifluoromethoxybenzamide                                        308           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,4-                                                          dimethoxybenzamide                                               309           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,6-                                                          dimethoxybenzamide                                               310           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,6-                                                          dichlorobenzamide                                                311           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2,6-                                                          dimethylbenzamide                                                312           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            methylthiobenzamide                                              313           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            methyl-3-thiophenecarboxamide                                    314           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-3-                                                            methyl-2-thiophenecarboxamide                                    315           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-                                                            methyl-3-furanecarboxamide                                       316           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-3-methyl-2-                                                   furanecarboxamide                                                317           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]benzeneacetamide                                 318           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-chlorobenzene-                                              acetamide                                                        319           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-methylbenzene-                                              acetamide                                                        320           N-[4-[(6,7-dihydro-5H-pyrrolo                                                  [1,2-a][1,5]benzodiazepin-5-yl)                                                carbonyl]phenyl]-2-methyl-3-                                                   thiopheneacetamide                                               ______________________________________                                    

EXAMPLE 321

5,6-Dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine

A mixture of 7.0 g of 5,6-dihydro-4H-triazolo-[4,3-a][(1,5]benzodiazepin-5-one in 25 ml of tetrahydrofuran is added 9 ml of 10 M borane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 6 hours, cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum and to the residue is added 100 ml of 2 N sodium hydroxide. The mixture is refluxed for 5 hours, chilled and extracted with dichloromethane. The extract is washed with 2 N citric acid, water and dried (Na₂ SO₄). The solvent is removed under vacuum to give a solid. The solid is purified by chromatography on silica gel to give the desired product.

EXAMPLE 322

N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5benzodiazepin-6(5H)-ylcarbonyl)phenyl]-2-methyl benzamide

To a mixture of 5 mmol of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and then 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NAHCO₃ and brine. The solution is dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product as a glass.

EXAMPLE 323

5,6-Dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4]triazolo-[4,3-a][1,5]benzodiazepin

To a mixture of 3 mmol of 5,6-dihydro-4H-[1,2,4]-triazolo[4,3-a][1,5]benzodiazepine in 10 ml of dichloromethane under argon is added 5 mmol of triethylamine. To the mixture is added dropwise 3,3 mmol of 4-nitrobenzoyl chloride in 3 ml of dichloromethane. The mixture is stirred at room temperature 3 hours and then washed with water, aqueous NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄) and the solvent removed under vacuum. The residue is purified by chromatography on silica gel to give the desired product as a solid.

EXAMPLE 324

5,6-Dihydro-6-(aminobenzoyl)-4H-[1,2,4]triazolo-[4,3-a]1,4]benzodiazepine

To a mixture of 5 mmol of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-[1,2,4]triazolo[4,3-a](1,4]benzodiazepine in 25 ml of ethanol is added 0.3 g of 10% Pd/C and 15 mmol of hydrazine. The mixture is refluxed for 3 hours, cooled and filtered through diatomaceous earth. The filtrate is concentrated in vacuo and the residue purified by chromatography on silica gel to give the desired product as a solid.

                  TABLE XII                                                        ______________________________________                                         The following Examples are prepared using                                      the conditions of Example 322 with the                                         appropriately substituted aroyl                                                chloride                                                                       Example                                                                        No.         Compound                                                           ______________________________________                                         325         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-chlorobenzamide                                                  326         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,5-dichlorobenzamide                                              327         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,4-dichlorobenzamide                                              328         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,3-difluorobenzamide                                              329         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-chloro-4-methylbenzamide                                         330         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methyl-4-chlorobenzamide                                         331         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,4-dimethylbenzamide                                              332         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,3-dimethylbenzamide                                              333         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methoxybenzamide                                                 334         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-trifluoromethoxybenzamide                                        335         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,3-dichlorobenzamide                                              336         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,4-dimethoxybenzamide                                             337         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,6-dimethoxybenzamide                                             338         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methoxy-4-chlorobenzamide                                        339         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-trifluoromethylbenzamide                                         340         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,6-dichlorobenzamide                                              341         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2,6-dimethylbenzamide                                              342         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methylthiobenzamide                                              343         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methyl-3-thiophenecarboxamide                                    344         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         3-methyl-2-thiophenecarboxamide                                    345         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methyl-3-furanecarboxamide                                       346         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methyl-3-furanecarboxamide                                       347         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         3-methyl-2-furanecarboxamide                                       348         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methoxybenzeneacetamide                                          349         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methylbenzeneacetamide                                           350         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-chlorobenzeneacetamide                                           351         N-[4-(4H-[1,2,4]triazolo[4,3-a][1,5]                                           benzodiazepin-6(5H)-ylcarbonyl)phenyl]                                         2-methyl-3-thiopheneacetamide                                      ______________________________________                                    

EXAMPLE 352

N-[4-(1-Methyl-4H-[1,2,4]triazolo[4,3-a][1,5benzodiazepin-6(5H)-ylcarbonyl)phenyl]-2-methyl benzamide

To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product.

EXAMPLE 353

N-[4-(1-Methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6(5H) -ylcarbonyl)phenyl]-2,4dichlorobenzamide

To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the desired product as a solid.

EXAMPLE 354

N-[4-(5H-Pyrrolo[2,1-c[1,4]benzodiazpin-10(11)-ylcarbonyl)phenyl]-3-cyclohexenecarboxamide

A mixture of 0.50 g of 10,11-dihydro-10(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.286 g of 3-cyclohexenecarbonyl chloride and 346 μl of triethylamine in 5 ml of dichloromethane is stirred at room temperature 16 hours. The mixture is diluted with 50 ml of dichloromethane and the solution washed with 20 ml of water, 2 N citric acid, 1 N NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo. The residue is chromatographed on thick layer silica gel plates to give a solid which is crystallized from ethyl acetate to give 0.34 g of crystals, m.p. 216-218° C.

EXAMPLE 355

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11) ylcarbonyl)phenyl]-5-methyl-2-thiophenecarboxamide

To a solution of 0.318 g of 5-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 μl of triethylamine. The mixture is stirred at room temperature 16 hours and diluted with 50 ml of dichloromethane. The solution is washed with 20 ml each of water, 2 N citric acid. 1 M NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to give a solid. The solid is crystallized from ethyl acetate to give 0.53 g of crystals, m.p. 235-238° C.

EXAMPLE 356

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11) ylcarbonyl)phenyl]-cyclohexylacetamide

To a solution of 0.318 g of cyclohexylacetyl chloride in 5 ml of dichloromethane cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 μl of triethylamine. The mixture is stirred at room temperature 16 hours and diluted with 50 ml of dichloromethane. The solution is washed with 20 ml each of water, 2 N citric acid. 1 N NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to give a solid. The solid is crystallized from ethyl acetate to give 0.52 g of crystals, m.p. 231-234° C.

EXAMPLE 357

N-[4-(5H-Pyrrolo[2,1-c][1,4benzodiazepin-10(11) ylcarbonyl)phenyl]-2-fluorobenzeneacetamide

To a solution of 0.342 g of 2-fluorophenylacetyl chloride in 5 ml of dichloromethane cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 μl of triethylamine. The mixture is stirred at room temperature 16 hours and diluted with 50 ml of dichloromethane. The solution is washed with 20 ml each of water, 2 N citric acid. 1 M NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to give a solid. The solid is crystallized from ethyl acetate to give 0.43 g of crystals, m.p. 204-207° C.

EXAMPLE 358

N-[4-(5H-Pyrrolo[2,1-c][1,4benzodiazepin-10(11) ylcarbonyl)phenyl]-cyclohexanecarboxamide

To a solution of 0.342 g of cyclohexanecarbonyl chloride in 5 ml of dichloromethane cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 μl of triethylamine. The mixture is stirred at room temperature 16 hours and diluted with 50 ml of dichloromethane. The solution is washed with 20 ml each of water, 2 N citric acid. 1 M NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated in vacuo to give a solid. The solid is crystallized from ethyl acetate to give 0.54 g of crystals, m.p. 202-204° C.

EXAMPLE 359

4-[N-Methyl-N-(2-methylbenzoylamino]benzoyl chloride

A solution of 6.72 g of 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoic acid in 20 ml of thionyl chloride is refluxed for one hour. The volatiles are removed in vacuo. Toluene is added to the residue and then the toluene removed in vacuo (repeated several 5 times) to give the 7.3 g of product as a brown oil.

EXAMPLE 360

4-[N-Methyl-N-(2-methylbenzoyl amino]benzoic acid

A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexane under argon to remove the oil. To the washed sodium hydride is added 5 ml of N,N-dimethylformamide. To this mixture is added dropwise a solution of 8.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 ml of N,N-di-methylformamide. The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours. The mixture is diluted with water and extracted with dichloromethane. The extract is dried (Na₂ SO₄), concentrated to reduce the volume and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 11 g of an oil (1:1 mixture of product and N,N-dimethylformamide). The preceding product, ethyl 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30 ml of methanol and 25 ml of 2 N NaOH added. The mixture is refluxed for 2 hours and the solvent removed. The residue is extracted with ether (discard) and the remaining residue dissolved in 50 ml of water. The basic solution is acidified with 2 N citric acid and the solid filtered off and washed with water. The product is air dried to give 6.72 g of crystals, m.p. 187-190° C.

As described for Example 360 but substituting the appropriate ethyl 4-[(N-aroyl)amino]benzoate, the following compounds are prepared.

EXAMPLE 361

4-[N-Methyl-N-(2-chlorobenzoyl)amino]benzoic acid

EXAMPLE 362

4-[N-Methyl-N-(2,5-dichlorobenzoyl)amino]benzoic acid

EXAMPLE 363

4-[N-Methyl-N-(2,4-dichlorobenzoyl)amino]benzoic acid

EXAMPLE 364

4-[N-Methyl-N-(2-chloro-4-methylbenzoyl)amino]-benzoic acid

EXAMPLE 365

4- [N-Methyl-N-(2-methyl-4-chlorobenzoyl)amino]-benzoic acid

EXAMPLE 366

4-[N-Methyl-N-(2,4-dimethylbenzoyl)amino]benzoic acid

EXAMPLE 367

4- [N-Methyl-N-(2,3-dimethylbenzoyl)amino]benzoic acid

EXAMPLE 368

4-[N-Methyl-N-(2-methoxybenzoyl)amino]benzoic acid

EXAMPLE 369

4-[N-Methyl-N-(2-trifluoromethoxybenzoyl)amino]-benzoic acid

EXAMPLE 370

4-[N-Methyl-N-(2,4-dimethoxybenzoyl)amino]-benzoic acid

EXAMPLE 371

4-[N-Methyl-N-(2-methoxy-4-chlorobenzoyl)amino]-benzoic acid

EXAMPLE 372

4-[N-Methyl-N-(2-methylthiobenzoyl)amino]-benzoic acid

EXAMPLE 373

4-[N-Methyl-N-(2-methylthiophen-3-ylcarbonyl)amino]-benzoic acid

EXAMPLE 374

4-[N-Methyl-N-(3-methylthiophene-2-ylcarbonyl)amino]-benzoic acid

EXAMPLE 375

4-[N-Methyl-N-(2-methylfuran-3-ylcarbonyl)amino]-benzoic acid

EXAMPLE 376

4-[N-Methyl-N-(3-methylfuran-2-ylcarbonyl)amino]-benzoic acid

EXAMPLE 377

4-[N-Methyl-N-(phenylacetyl)amino]benzoic acid

EXAMPLE 378

4-[N-Methyl-N-(2-chlorophenylacetyl)amino]benzoic acid

EXAMPLE 379

4-[N-Methyl-N-(2-methoxyphenylacetyl)amino]-benzoic acid

EXAMPLE 380

4-[N-Methyl-N-(2-methylphenylacetyl)amino]-benzoic acid

EXAMPLE 381

4-[N-Methyl-N-(cyclohexylcarbonyl)amino]-benzoic acid

EXAMPLE 382

4-[N-Methyl-N-(3-cyclohexenecarbonyl)amino]-benzoic acid

EXAMPLE 382

4-[N-Methyl-N-(cyclohexylacetyl)amino]-benzoic acid

EXAMPLE 384

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methylbenzamide

A mixture of 0.27 g of 10,11-dihydro-5H-pyrrolo[2,1-c][(1,4]benzodiazepine, 0.518 g of 4-(N-methyl-N-(2-methylbenzoyl)amino]benzoyl chloride, 0.182 g of triethylamine and 7 ml of tetrahydrofuran is stirred at room temperature for 3 hours. To the mixture is added 0.29 g of 4-[N-methyl-N-(2-methylbenzoyl) amino]benzoyl chloride and 0.10 g of triethylamine in 2 ml of dichloromethane and the mixture stirred for 2 days. The mixture is poured into water and extracted with dichloromethane. The extract is washed with water, 1 N HCl, 1 N NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo and the residue crystallized from dichloromethane-hexane to give 0.38 g of crystals, m.p. 168-170° C.

As described for Example 384, but substituting the appropriate aroyl chloride, the following compounds are prepared.

EXAMPLE 385

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chlorobenzamide

EXAMPLE 386

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,5-dichlorobenzamide

EXAMPLE 387

N-[4-(5H-Pyrrolo[2,1c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chloro-4-methylbenzamide

EXAMPLE 388

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-4-chlorobenzamide

EXAMPLE 389

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,4-dimethylbenzamide

EXAMPLE 390

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,3-dimethylbenzamide

EXAMPLE 391

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxybenzamide

EXAMPLE 392

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10 (11H)-ylcarbonyl)phenyl]-N-methyl-2-trifluoromethoxybenzamide

EXAMPLE 393

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2,4-dimethoxybenzamide

EXAMPLE 394

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxy-4-chlorobenzamide

EXAMPLE 395

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2 -methylthiobenzamide

EXAMPLE 396

N-[4- (5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3 -thiophene-carboxamide

EXAMPLE 397

N-4-(5H-Pyrrolo[2,1c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-3-methyl-2-thiophene-carboxamide

EXAMPLE 398

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3 -furane-carboxamide

EXAMPLE 399

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10 (11H) -ylcarbonyl)phenyl]-N-methylbenzeneacetamide

EXAMPLE 400

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-chlorobenzeneacetamide

EXAMPLE 401

N-[4-(5-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methoxybenzeneacetamide

EXAMPLE 402

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methylbenzeneacetamide

EXAMPLE 403

N-[4-(5H-Pyrrolo[2,l-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-2-methyl-3-thiophene-acetamide

EXAMPLE 404

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methylcyclohexanecarboxamide

EXAMPLE 405

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methylcyclohexylacetamide

EXAMPLE 406

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-N-methyl-3-cyclohexenecarboxamide

EXAMPLE 407

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-2-methylphenyl]-2,4-dichlorobenzamide

A mixture of 0.40 g of 10,11-dihydro-10-(3-methyl-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.40 g of 2,4-dichlorobenzoyl chloride and 0.75 g of diisopropylethylamine in 50 ml of dichloromethane is stirred at room temperature for 16 hours. The mixture is washed with water, dried (MgSO₄) and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and hexane added to give crystals. Recrystallization from dichloromethane-hexane gives 0.52 g of crystals, m.p. 213-215° C.

EXAMPLE 408

1-(2-Nitrophenyl)-1H-pyrrole-2-carboxaldehyde

A sample of 4.7 g of sodium hydride (60% in oil) is washed with hexane (under argon). To the sodium hydride is added 200 ml of dry N,N-dimethyl-formamide and the mixture is chilled to 0° C. To the mixture is added 10.11 g of pyrrole-2-carboxaldehyde in small portions. The mixture is stirred 10 minutes and 15.0 g of 1-fluoro-2-nitrobenzene added dropwise. After the addition, the mixture is stirred at room temperature 16 hours and the mixture concentrated (65° C.) under high vacuum. To the residue is added 400 ml of dichloromethane and the mixture washed with 150 ml each of H₂ O, brine and dried (Na₂ SO₄). The solvent is removed in vacuo to give a yellow solid. Crystallization from ethyl acetate-hexane (9:1) gives 17.0 g of light yellow crystals, m.p. 119°-122° C.

EXAMPLE 409

4,10-Dihydro-5-pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepine

To an ice cooled mixture of 2.1 g of pyrrole-2-carboxylic acid and 3.2 g of methyl 3-amino-thiophene-2-carboxylate in 40 ml of dry dichloromethane is added 4 g of N,N-dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 3 hours and 30 filtered. The filter cake is washed with dichloromethane and then extracted twice with 60 ml of acetone. The acetone extract is concentrated to dryness to give 0.8 g of solid, m.p. 214-218° C. To a suspension of the preceding compound (1.19 g) in 20 ml of dry tetrahydrofuran is added 0.2 g of sodium hydride (60% in oil). After the hydrogen evolution, the mixture is stirred and refluxed for 4.5 hours, cooled and poured into ice-water. The precipitated solid is filtered and the solid triturated with petroleum ether (bp 30-60° C.) to give 0.75 g of 4,10-dihydro-4,10-dioxo-5H -pyrrolo-[1,2-a]thieno[3,2-e][1,4]diazepine as a solid, m.p. 280-290° C. The preceding compound (0.362 g) is added to an ice-water cooled solution of 1 M diborane in tetrahydrofuran. The mixture is stirred at room temperature for 65 hours. The solution is concentrated to dryness and ice-water added to the residue. The mixture is acidified with dilute HCl, stirred and then basified with solid NAHCO₃. The mixture is filtered to give 0.223 g of a solid (foam) m.p. 80-85° C.

EXAMPLE 410

10,11-Dihydro-5H-1,2,4-triazolo[3,4-c][1,4]-benzodiazepine

A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide is heated at 150-155° C. for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70-78° C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 50 ml of methanol. The mixture is shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid, m.p. 167-170° C.

A mixture of the preceding compound (1.6 g) and 0.84 g of phosphorus pentasulfide in 10 ml of dry (dried over KOH) pyridine is stirred and heated at 80-85° C. for 15 minutes. The mixture is poured into water and stirred for 30 minutes. Filtration gives 1.0 g of 1,2,4,5-tetrahydro-3H-1,4-benzodiazepin-3-thione as yellow solid, m.p. 150-153° C.

The preceding compound (0.5 g) and 0.5 g of N-formylhydrazine in 6 ml of dry n-butanol is refluxed for 16 hours and the solvent removed. The gummy residue is triturated with cold water and the mixture filtered. The solid is triturated with acetone to give 0.19 g of yellow solid, m.p. 232-237° C.

EXAMPLE 411

4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepine

A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of n-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162-165° C.

EXAMPLE 412

4,5-Dihydro-6H-imidazo[1,2-a][1,5 ]benzodiazepine

A mixture of 30 g of acrylic acid, 33 g of o-phenylenediamine is heated on a steam bath for 1.5 hours and the cooled black mixture triturated with ice-water. The aqueous phase is decanted and ice and aqueous ammonium hydroxide added to the residue. The mixture is extracted with dichloromethane and the extract concentrated to dryness. The residue is triturated with carbon tetrachloride and filtered. The oily solid is triturated with a small amount of ethanol to give 9.7 g of a solid. Trituration of the solid with ethyl acetate gives 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one as an impure solid, m.p. 75-107° C.

A mixture of the preceding compound (11.3 g) and 5.9 g of phosphorus pentasulfide in 70 ml of dry pyridine is stirred and heated at approximately 80° C. for 20 minutes. The mixture is poured into water and the mixture stirred for 30 minutes. Filtration gives 8.6 g of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione as a solid, m.p. 154-157° C.

A mixture of the preceding compound (0.70 g), 1.0 g of aminoacetaldehyde dimethyl-acetal and 15 mg of 4-methylbenzenesulfonic acid monohydrate in 6 ml of dry n-butanol is refluxed for 4 hours and the solvent removed under vacuum. The residue is heated (refluxed) with 10 ml of 3 N hydrochloric acid for 55 minutes. Ice is added to the cooled mixture and the mixture made basic with solid NAHCO₃. The mixture is extracted with dichloromethane and the extract dried (Na₂ SO₄). The solvent is removed to give an orange syrup which solidified on standing. The oily solid is triturated with acetone to give a light yellow solid (0.185 g) m.p. 119-122° C.

EXAMPLE 413

1-(2-Nitrophenyl)-2-pyrroleacetic acid, ethyl ester

To a stirred mixture of 1.88 g of 1-(2-nitrophenyl)pyrrole, 4.80 g of ethyl iodoacetate and 2.22 g of FeSO₄.7H₂ O in 40 ml of dimethyl sulfoxide is added dropwise 10 ml of 301 hydrogen peroxide while keeping the reaction mixture at room temperature with a cold water bath. The mixture is stirred at room temperature for one day. An additional 2.4 g of ethyl iodoacetate, 1.1 g of FeSO₄.7H₂ O and 5 ml of 30% hydrogen peroxide is added and the mixture stirred at room temperature for 1 day. The mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water, brine and dried (Na₂ SO₄). The solvent is removed and the residue (2.12 g) chromatographed on silica gel with ethyl acetate-hexane (1:4) as solvent to give 0.30 g of product as a brown gum.

EXAMPLE 414

6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one

To a solution of 0.8 mmol of 1-(2-nitrophenyl)-2-pyrroleacetic acid, ethyl ester in 3 ml of ethanol is added stannus chloride dihydrate (SnCl₂. 2H₂ O) in 2 ml of concentrated hydrochloric acid (with cooling in water bath). The mixture is stirred at room temperature for 5 hours and chilled in an ice bath. To the mixture is added slowly saturated sodium carbonate solution. The solid which precipitates is filtered and the solid washed with water and then extracted with ethyl acetate. The ethyl acetate extract is dried (Na₂ SO₄) and the solvent removed to give 0.16 g of solid which is triturated with ether to give 0.11 g of product as an off-white solid.

EXAMPLE 415

6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine

To a solution of 0.070 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-6-one in 2 ml of tetrahydrofuran is added 0.45 ml of a 2.0 M solution of diborane-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 3 hours, poured into water and make basic with 2 N NaOH. The tetrahydrofuran is removed under vacuum and the residual aqueous mixture extracted with diethyl ether. The extract is washed with brine, dried (Na₂ SO₄) and the solvent removed to give 0.065 g of a colorless oil; one spot by thin layer chromatography (silica gel) with ethyl acetate-hexane (1:2) as solvent (Rf 0.81).

EXAMPLE 416

10,11-Dihydro-10-(2-chloro-4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 5.0 g of 10,11-dihydro-10-(2-chloronitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 15.4 g of stannus chloride and 170 ml of ethanol is heated at 70-80° C. for 1 hour. The mixture is chi8lled (ice bath) and made basic with 1 M NaHCO₃ solution (350 ml) and then stirred at room temperature for 1 hour. The mixture is brought to pH 5 with acetic acid and extracted with 500 ml of ethyl acetate and with 300 ml of ethyl acetate. The combined extract is washed with 250 ml of brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate is concentrated to dryness and the residue dissolved in 200 ml of hot chloroform-methanol (1:1) and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated under vacuum to give 4.36 g (after drying under vacuum at 60° C. overnight) of product as a white solid. A sample is recrystallized from chloroform-methanol to give white crystals, m.p. 210-212° C.

EXAMPLE 417

4-[(5-Fluoro-2-methylbenzoyl)amino]benzoic acid

A mixture of 0.60 g of ethyl 4-[(5-fluoro-2-methylbenzoyl)amino]benzoate 0.60 ml of 10 N NaOH, 25 ml of water and 50 ml of absolute ethyl alcohol is heated on a steam bath for 1 hour, cooled and acidified with acetic acid. The resulting solid is filtered and dried in vacuo at 60-80° C. to give 0.47 g of the desired product as a solid, m.p. 272-275° C.

The following Examples are prepared using the conditions of Example 417.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         418          4-[(3-fluoro-2-methylbenzoyl)amino]-                                           benzoic acid, m.p. 309-311° C.                             419          4-[(5-fluoro-2-methylbenzoyl)amino]-2-                                         chlorobenzoic acid, m.p. 247-249° C.                       420          4-[3-fluoro-2-methylbenzoyl)amino]-2-                                          chlorobenzoic acid, m.p. 260-263° C.                       421          4-[[4-fluoro-3-(trifluoromethyl)]benzo-                                        yl]amino]-2-chlorobenzoic acid                                    422          4-[[2-fluoro-3-(trifluoromethyl)]benzo-                                        yl]amino]-2-chlorobenzoic acid                                    423          4-[(2,5-difluorobenzoyl)amino]-2-chloro-                                       benzoic acid                                                      424          4-[(2,5-dichlorobenzoyl)amino]-2-chloro-                                       benzoic acid                                                      425          4-[(2,3-dimethylbenzoyl)amino]-2-chloro-                                       benzoic acid                                                      426          4-[(2,3-dichlorobenzoyl)amino]-2-chloro-                                       benzoic acid                                                      427          4-[(2,5-dimethylbenzoyl)amino]-2-chloro-                                       benzoic acid                                                      428          4-[2,3-difluorobenzoyl)amino]-2-chloro-                                        benzoic acid                                                      ______________________________________                                    

EXAMPLE 429

4-[2,4-Dichlorobenzoyl)amino]-2-chlorobenzoic acid

To a stirred mixture of 5.19 g of 2-chloro-4-aminobenzoic acid in 150 ml of methylene chloride is added 7.86 g of N,N-diisopropylethylamine and 12.67 g of 2,4-dichlorobenzylchloride and stirring continued for 18 hours. Water is added to the filtrate and the organic layer dried with Na₂ SO₄ and concentrated in vacuo to give 13.68 g of the desired product, m.p. 171-175° C.

The following Examples are prepared using the conditions of Example 429.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         430          4-[(2-methylbenzoyl)amino]-2-chloro-                                           benzoic acid, m.p. 196-199° C.                             431          4-[(2-methylbenzoyl)amino]-3,5-di-                                             methylbenzoic acid, m.p. 286-289° C.                       432          4-[(2,4-dichlorobenzoyl)amino]-3,5-                                            dimethylbenzoic acid, m.p. 209-212° C.                     433          4-[(2-methylbenzoyl)amino]-3-chloro-                                           benzoic acid, m.p. 199-202° C.                             434          4-[(2,5-dichlorobenzoyl)amino]-2-                                              chlorobenzoic acid                                                435          4-[(3-fluoro-2-methylbenzoyl)amino]-3-                                         chlorobenzoic acid, m.p. 225-227° C.                       436          4-[(5-fluoro-2-methylbenzoyl)amino]-3-                                         chlorobenzoic acid, m.p. 182-185° C.                       437          4-[(2,3-dimethylbenzoyl)amino]-3-                                              chlorobenzoic acid                                                438          4-[(2,3-dichlorobenzoyl)amino]-3-                                              chlorobenzoic acid                                                439          4-[(2,5-dimethylbenzoyl)amino]-3-                                              chlorobenzoic acid                                                440          4-[[4-fluoro-2-(trifluoromethyl)benzoyl]                                       amino]-3-chlorobenzoic acid                                       441          4-[[3-fluorobenzoyl]amino]-2-chloro-                                           benzoic acid, m.p. 249-252° C.                             442          4-[[2-(trifluoromethyl)benzoyl]amino]-                                         3-chlorobenzoic acid                                              ______________________________________                                    

EXAMPLE 443

Ethyl 10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 25 ml of absolute ethanol is added 0.12 g of sodium metal with stirring followed by 0.68 g of 10,11-dihydro-10-(2-chloro-4-nitrobenzoyl)-[3-(trichloroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

Stirring is continued for 18 hours. The volatiles are removed in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated, dried with Na₂ SO₄ and filtrate heated on a steam bath while hexane is added to give 0.45 g of the desired product as a solid, m.p. 165-166° C.

The following Examples are prepared using the conditions of Example 443.

    ______________________________________                                         Example No.   Compound                                                         ______________________________________                                         444           ethyl 10,11-dihydro-10-(3-methyl-4-                                            nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepine-3-carboxylate, m.p.                                             200-202° C.                                               445           ethyl 10,11-dihydro-10-(2-methyl-4-                                            nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepine-3-carboxylate                                     446           ethyl 10,11-dihydro-10-(2-chloro-4-                                            nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepine-3-carboxylate                                     447           ethyl 10,11-dihydro-10-(3-chloro-4-                                            nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepine-3-carboxylate                                     ______________________________________                                    

EXAMPLE 448

10,11-Dihydro-10-(3-methyl-4-nitrobenzoyl)-[3-trichloroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 3.47 g of 10,11-dihydro-10(4-nitro-3-methylbenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine in 50 ml of methylene chloride is added 3.40 g of trichloroacetic anhydride and stirring continued for 18 hours. Water is added and the -separated organic layer washed with saturated sodium bicarbonate, dried with Na₂ SO₄ and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 4.07 g of the desired product as a solid. MASS SPEC (CI) 491(MH⁺).

The following Examples are prepared using the conditions of Example 448.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         449          10,11-dihydro-10-(4-nitrobenzoyl)-[3-                                          (trichloroacetyl)]-5H-pyrazolo[2,1-c]-                                         [1,4]benzodiazepine, m.p. 122-123° C.                      450          10,11-dihydro-10-(2-chloro-4-nitro-                                            benzoyl)-[3-(trichloroacetyl)]-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepine, m.p.                                        149-151° C.                                                ______________________________________                                    

EXAMPLE 451

10,11-Dihydro-10-(4-nitrobenzoyl)- [3-(trifluoroacetyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.50 g of 10,11-dihydro-10(4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 10 ml of methylene chloride is cooled in an ice bath and 2.0 g of trifluoroacetic anhydride added. The bath is removed and the reactants stirred for 18 hrs, partitioned with saturated sodium bicarbonate and the separated organic layer dried with Na₂ SO₄ then passed through a short pad of hydrous magnesium silicate. The filtrate is heated at the boil while hexane is added to give 0.40 g of the desired product, m.p. 169-170° C.

The following Examples are prepared using the conditions of Example 451.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         452          10,11-dihydro-10-(2-chloro-4-nitro-                                            benzoyl)[3-(trifluoroacetyl)]-5H-                                              pyrrolo[2,1-c][1,4]benzodiazepine, m.p.                                        151-153° C.                                                453          10,11-dihydro-10-(3-chloro-4-nitro-                                            benzoyl)[3-(trifluoroacetyl)]-5H-                                              pyrrolo[2,1-c)][1,4]benzodiazepine                                454          10,11-dihydro-10-(2-methyl-4-nitro-                                            benzoyl)[3-(trifluoroacetyl)]-5H-                                              pyrrolo[2,1-c][1,4]benzodiazepine                                 ______________________________________                                    

EXAMPLE 455

10,11-Dihydro-10-(3-methoxy-4-nitrobenzoyl)-5H-pyrrolo[2,1c][1,4]benzodiazepine

A mixture of 5.0 g of 3-methoxy-4-nitrobenzoic acid and 5.0 g of thionyl chloride is heated under argon for 1 hour. The volatiles are removed in vacuo to give 2.85 g of a 3-methoxy-4-nitrobenzoyl chloride as a residue which is dissolved in 50 ml of methylene chloride. To the preceding solution is added with stirring 1.75 g of N,N-diisopropylethylamine followed by 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine. The reaction mixture is stirred under argon for 18 hours and diluted with saturated sodium bicarbonate. The organic layer is dried with Na₂ SO₄ and passed through a short pad of hydrous magnesium silicate. While boiling, hexane is added to the filtrate to give, upon cooling, 3.39 g of the desired product as a solid, m.p. 191-192° C.

The following Examples are prepared using the conditions of Example 455.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         456          10,11-dihydro-10-(2-methoxy-4-nitro-                                           benzoyl)-5H-pyrrolo[2,1-c][1,4]benzo-                                          diazepine                                                         457          10,11-dihydro-10-(2-methyl-4-nitro-                                            benzoyl)-5H-pyrrolo[2,1-c][1,4]-                                               benzodiazepine                                                    458          10,11-dihydro-10-(3-methoxy-6-chloro-                                          4-nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                        benzodiazepine                                                    459          10,11-dihydro-10-(3-methoxy-6-methyl-4-                                        nitrobenzoyl)-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepine                                                    ______________________________________                                    

EXAMPLE 460

10,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 3.24 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl) -5H-pyrrolo(2,1-c][1,4]benzodiazepine, 0.35 g of 10 Pd/c and 0.60 g of anhydrous hydrazine in 100 ml of absolute ethyl alcohol and heated on a steam bath for 1 hour. The hot reaction mixture is filtered through diatomaceous earth and the filtrate evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is dried with Na₂ SO₄ and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate while heating on a steam bath to give 2 g of crystals, m.p. 184-185° C.

The following Examples are prepared using the conditions of Example 460.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         461          10,11-dihydro-10-(4-amino-2-chloro-                                            benzoyl)-5H-pyrrolo[2,1-c][1,4]benzo-                                          diazepine, m.p. 197-199° C.                                462          10,11-dihydro-10-(4-aminobenzoyl)[3-                                           (trifluoroacetyl)]-5H-pyrrolo[2,1-c]-                                          [1,4]benzodiazepine, m.p. 200-206° C.                      463          ethyl 10,11-dihydro-10-(4-amino-3-                                             methylbenzoyl)-5H-pyrrolo[2,1-c]-                                              [1,4]benzodiazepine-3-carboxylate, m.p.                                        210-211° C.                                                464          ethyl 10,11-dihydro-10-(4-aminobenzoyl)-                                       5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-                                        carboxylate, m.p. 174-175° C.                              ______________________________________                                    

EXAMPLE 465

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-5-fluoro-2-methylbenzamide

To a stirred solution of 500 mg of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 3 ml of methylene chloride, cooled to 0° C., under argon, is added 346 μl of triethylamine followed by the addition of 340 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride. The cooling bath is removed and stirring continued for 18 hours. After cooling to 0° C., an additional 342 mg of 2-methyl-5-fluorobenzoyl chloride in 2 ml of methylene chloride is added. The cooling bath is removed and stirring continued for 18 hours. The volatiles are removed in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 2 N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na₂ SO₄ and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is crystallized from ethyl acetatehexane to give 295 mg of the desired product as a white solid, m.p. 170-180° C.

The following Examples are prepared using the conditions of Example 465 with the appropriately substituted aroyl chloride.

    ______________________________________                                         Example No.                                                                               Compound                                                            ______________________________________                                         466        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodia-                                          zepin-10(11H)-ylcarbonyl)phenyl]-3-                                            fluoro-2-methylbenzamide, m.p. 194-208° C.                   467        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2,3-di-                                         methylbenzamide, m.p. 168-170° C.                            468        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2,3-                                            dichlorobenzamide, m.p. 219-222° C.                          469        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2,6-di-                                         chlorobenzamide, m.p. 174-182° C.                            470        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl-3-chlorophenyl]-                                        2-methylbenzamide, m.p. 190-195° C.                          471        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl-3-chlorophenyl]-                                        2,4-dichlorobenzamide, m.p. 144-160° C.                      472        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl-2,6-dimethyl                                            phenyl]-2-methylbenzamide, amorphous                                           solid                                                               473        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl-2,6-dimethyl                                            phenyl]-2,4-dichlorobenzamide, amorphous                                       solid                                                               474        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-3-(tri-                                         fluoromethyl)benzamide, amorphous                                              solid                                                               475        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chloro-                                              phenyl]-3-methylthiophene-2-carboxamide                             476        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-3-                                              chlorothiophene-2-carboxamide, solid;                                          MASS SPEC (CI): 448(M + H)                                          477        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-methoxy-                                             phenyl]-2-methylbenzamide, m.p.                                                184-186° C.                                                  478        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-methoxy-                                             phenyl]-2,4-dichlorobenzamide, m.p.                                            192-194° C.                                                  479        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-methoxy-                                             phenyl]-3-fluoro-2-methylbenzamide                                             m.p. 203-204° C.                                             480        N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                       5-nitrobenzamide, m.p. 110-160° C.                                      (amorphous solid)                                                   267        N-(5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-                                        diazepin-4(10H)-ylcarbonyl)phenyl]-                                            2-methylbenzamide, m.p. 162-188° C.                                     (amorphous solid)                                                   274        N-[4-(5H-pyrrolo[1,2-a]thieno[3,2-e]-                                          [1,4]-diazepin-4(10H)-ylcarbonyl)-                                             phenyl]-2,4-dichlorobenzamide, m.p.                                            105-190° C.                                                  ______________________________________                                    

EXAMPLE 481

N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-3-fluoro-2-methyl-benzamide

To a solution of 1.50 g of 10,11-dihydro-5 H-pyrrolo [2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.23 g of N,N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.08 g of [4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous and is stirred at room temperature for 18 hours. Water is added and the separated organic layer washed with saturated sodium bicarbonate, dried with Na₂ SO₄ and passed through a short pad of hydrous magnesium silicate two times. The methylene chloride is removed in vacuo to give 3.81 g of a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 200-205° C.

EXAMPLE 482

N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methyl-benzamide

To a solution of 1.84 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 25 ml of methylene chloride is added 1.30 g of N,N-diisopropylethylamine. While cooling in an ice bath, a solution of 3.45 g of [4-[(2-methyl-5-fluorobenzoyl)amino]-2-chlorobenzoyl chloride in 50 ml of methylene chloride is added. The reaction mixture becomes homogeneous after 5 minutes and is stirred at room temperature for 18 hours. Water is added and the separated organic layer washed with saturated sodium bicarbonate, dried with Na₂ SO₄ and passed through a short pad of hydrous magnesium silicate. The methylene chloride is removed in vacuo to give 4.60 g of the desired product as a glass. A sample is crystallized from ethyl acetate to give crystalline solid, m.p. 191-195° C.

EXAMPLE 483

4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid

A solution of 0.92 g of 10,l1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.19 g of monomethyl terephthaloyl chloride in 20 ml of pyridine is refluxed for 2 hours. The mixture is chilled and 1 N HCl added until the pH is 5. The mixture is filtered and washed with water to give 1.53 g of solid. Recrystallization from dichloromethane-hexane gives crystals, m.p. 186-188° C. of methyl 4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-yl-carbonyl)benzoate.

A mixture of 1.83 g of the preceding compound, 8 ml of 2 N NaOH and 14 ml of methanol is refluxed for 0.5 hour and then concentrated under vacuum. The residue is extracted with ether and the aqueous layer acifidied with 2 N citric acid. The mixture is filtered and the solid washed with water and dried (60° C. under vacuum) to give 1.61 g of crystals, m.p. 210-214° C.

EXAMPLE 484

N-(2-Methylphenyl)-4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)benzamide

A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.111 g of triethylamine, 0.107 g of o-toluidine, and 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath overnight. The mixture is washed with water, 1 M NAHCO₃, 1 N HCl, brine and dried (Na₂ SO₄). The dichloromethane solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is crystallized from dichloromethane-hexane to give 0.23 g of white crystals, m.p. 228-231° C.

EXAMPLE 485

N-(2,3-Dimethylphenyl)-4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H) -ylcarbonyl)benzamide

A mixture of 0.332 g of 4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoic acid, 0.222 g of triethylamine, 0.157 g of 2,3-dimethylaniline hydrochloride, 0.15 ml of diethylphosphoryl cyanide in 20 ml of dichloromethane is heated on a steam bath for 3 hours. The mixture is washed with H₂ O, 1 M NaHCO₃, H₂, 1 N HCl, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness under vacuum and the residue crystallized from dichloromethane-hexane to give 0.11 g of crystals, m.p. 239-240° C.

EXAMPLE 486

N-[4-[(4,5-Dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]-benzodiazepin-6-yl)carbonyl)phenyl]-2-methylbenzoate

A mixture of 0.246 g of [4-(2-methylbenzoyl)-amino]benzoyl chloride, 0.14 g of 4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine and 2 ml of pyridine is heated on a steam bath for 4.5 hours and heated (oil bath) at 110° C. overnight. The mixture is chilled and poured into water. The mixture is neutralized with 1 N HCl and filtered. The solid is washed with dichloromethane and the dichloromethane filtrate evaporated under vacuum to give 0.151 g of product, MASS SPEC (FAB) 424.2(M+H).

EXAMPLE 487

N-[4-(Pyrrolo[1,2-a]quinoxalin-5(4H)-ylcarbonyl)-phenyl]-2,3-dichlorobenzamide

As described for Example 157, 0.47 g of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline, 346 μl of triethylamine and 5 ml of dichloromethane are chilled (ice bath) and 0.415 g of 2,3-dichlorobenzoyl chloride in 2 ml of dichloromethane added. After stirring overnight, an additional 346 μl of triethylamine is added and an additional 0.415 g of 2,3-dichlorobenzoyl chloride added. The mixture is stirred for 2 hours, diluted with 50 ml of dichloromethane and the solution washed with 20 ml each of H₂ O, 2 N citric acid, 1 M NaHCO₃ and brine. The organic layer is dried (Na₂ SO₄) and filtered through a thin pad of hydrous magnesium silicate-and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as solvent to give 0.100 g of white solid, m.p. 230-240° C.

EXAMPLE 488

10-[4-[[(2-Chlorophenyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.418 g of 2-chlorobenzenesulfonyl chloride in 5 ml of dichloromethane, cooled to 0° C. is added 0.50 g of 10,11-dihydro-10-(4-amino-benzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.346 μl of triethylamine. The mixture is stirred at room temperature overnight and diluted with 50 ml of dichloromethane. The mixture is washed with 20 ml each of H₂ O, 2 N citric acid, 1 M NaHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer silica gel plates (4) with the solvent ethyl acetate-hexane (1:1) to give a solid. Crystallization from ethyl acetate gives 0.165 g of white crystals, m.p. 206-210° C.

EXAMPLE 489

Methyl 4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)benzoate

To a cooled solution of 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 346 μl of triethylamine in 5 ml of dichloromethane is added 0.394 g of mono methyl terephthaloyl chloride. The mixture is stirred overnight under argon and diluted with 50 ml of dichloromethane. The mixture is washed with 20 ml each of H₂ O, 2 N citric acid, 1 M NAHCO₃, brine and dried (Na₂ SO₄). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness and the residue crystallized from ethyl acetate to give 0.50 g of white crystals, m.p. 224-228° C.

EXAMPLE 490

N-(Dimethylamino)methyl]-N-(4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H) -ylcarbonyl)phenyl]-2,4-dichlorobenzamide

To a suspension under argon of 0.072 g of sodium hydride (60% in oil) in 10 ml of tetrahydrofuran is added 0.71 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide and the mixture stirred at room temperature for 1 hour. To the mixture is added N,N-dimethylmethylene-ammonium iodide and the mixture stirred 20 hours. The mixture is diluted with diethyl ether (30 ml), filtered and the filtrate concentrated under vacuum. The residue is triturated with hexane to give 0.76 g of white solid, m.p. 126-129° C.

EXAMPLE 491

10-[4-[(Diphenylphosphinyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo-(2,1-c][1,4]benzodiazepine

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][(1,4]benzodiazepine 0.060 g of triethylamine and 0.12 g of diphenylphosphinyl chloride in 2 ml of dichloromethane is stirred at room temperature for 2 hours and then 1 N NaOH is added. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na₂ SO₄). The solvent is removed and the residue triturated with ether-hexane to give 0.16 g of a white solid.

EXAMPLE 492

10-[4-[Diphenylphosphinyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo(2,1-c][1,4]benzodiazepine

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][(1,4]benzodiazepine and 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.14 g of diphenoxyphosphinyl chloride. The mixture is stirred at room temperature for 2 hours and 1 N NaOH added. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na₂ SO₄). The solvent is removed to give a solid. Trituration with ether-hexane gives 0.20 g of product as a white solid.

EXAMPLE 493

10-[4-[[(2,5-Dichlorophenyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 0.050 g of triethylamine and 0.083 g of 2,5-dichlorobenzenesulfonyl chloride in 2 ml of dichloromethane is stirred at room temperature for 1 hour and then 4 mg of 4-(N,N-dimethylamino)pyridine is added. After another hour, 93 mg of 2,5-dichlorobenzenesulfonyl chloride is added along with 50 mg of triethylamine. The mixture is stirred at room temperature for 2 days and 1 N NaOH added. The mixture is extracted with ethyl acetate and the extract washed with 50% ammonium chloride solution, brine and dried (Na₂ SO₄). The solvent is removed to give 0.30 g of solid. Trituration with ether-hexane gives 0.26 g of solid. This solid is dissolved in a mixture of 5 ml of tetrahydrofuran, 1 ml of methanol, 1 ml of 1 N NaOH and the mixture stirred for 18 hours at room temperature. The organic solvents are removed and the mixture extracted with ether acetate. The extract is washed with NaHCO₃, brine and dried (Na₂ SO₄). The solvent is removed and the residue (0.16 g) triturated with ether to give 0.14 g of yellow solid.

EXAMPLE 494

10-[4-[[(Phenylmethyl)sulfonyl]amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.10 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.060 g of triethylamine in 2 ml of dichloromethane is added 0.10 g of α-toluenesulfonyl chloride. The mixture is stirred at room temperature for 2 hours and 1 N NaOH is added. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na₂ SO₄). The solvent is removed and the residue (0.20 g) is chromatographed on silica gel with the solvent ethyl acetate-hexane (3:2) to give 0.080 g of product as a white solid and 0.080 g of 10-[4-[[bis-(phenylmethyl)sulfonyl]amino]benzoyl]10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as a white solid. The preceding compound in methanol, 2 N NaOH is heated on a steam bath, the solvent removed and the basic aqueous residue extracted with ethyl acetate to give an additional amount of the product.

EXAMPLE 495

Ethyl 4-[(2-methylbenzoyl)amino]-3-chlorobenzoate

A mixture of 8.26 g of ethyl 4-aminobenzoate, 8.26 g of N-chlorosuccinimide in 50 ml of dichloromethane is refluxed overnight. The mixture is washed with saturated NaHCO₃ solution and dried (Na₂ SO₄). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and hexane added. Chilling gives 7.38 g of ethyl 3-chloro-4-aminobenzoate, m.p. 82-83° C.

To the preceding compound (3.66 g), 3.0 g of diisopropylethylamine in 50 ml of dichloromethane is added 3.55 g of 2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature overnight, washed with H₂ O, NaHCO₃ and dried (Na₂ SO₄). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated and diluted with hexane. Chilling gives 4.71 g of the product as crystals, 129-130° C.

The following Examples are prepared using the conditions of Example 495.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         496          Ethyl 4-[(2-chlorobenzoyl)amino]-3-                                            chlorobenzoate                                                    497          Ethyl 4-[(2,5-dichlorobenzoyl)amino]-                                          3-chlorobenzoate                                                  498          Ethyl 4-[(2,4-dichlorobenzoyl)amino]-3-                                        chlorobenzoate                                                    499          Ethyl 4-[(3,5-dichlorobenzoyl)amino]-3-                                        chlorobenzoate                                                    500          Ethyl 4-[(2-methyl-4-chlorobenzoyl)-                                           amino]-3-chlorobenzoate                                           501          Ethyl 4-[(2,3-dimethylbenzoyl)amino]-                                          3-chlorobenzoate                                                  502          Ethyl 4-[(2-methoxybenzoyl)amino]-3-                                           chlorobenzoate                                                    503          Ethyl 4-[(2-(trifluoromethoxy)benzoyl]-                                        amino]-3-chlorobenzoate                                           504          Ethyl 4-[(2-methoxy-4-chlorobenzoyl)-                                          amino]-3-chlorobenzoate                                           505          Ethyl 4-[[2-(methylthio)benzoyl]amino]-                                        3-chlorobenzoate                                                  506          Ethyl 4-[(2-methylbenzeneacetyl]amino]-                                        3-chlorobenzoate                                                  507          Ethyl 4-[[4-fluoro-2-(trifluoromethyl)-                                        benzoyl]amino]-3-chlorobenzoate                                   508          Ethyl 4-[[4-fluoro-3-(trifluoromethyl)-                                        benzoyl]amino]-3-chlorobenzoate                                   509          Ethyl 4-[[2-fluoro-3-(trifluoromethyl)-                                        benzoyl]amino]-3-chlorobenzoate                                   510          Ethyl 4-[(3-fluoro-2-methylbenzoyl)-                                           amino]-3-chlorobenzoate                                           511          Ethyl 4-[(2,3-dichlorobenzoyl)amino]-                                          3-chlorobenzoate                                                  512          Ethyl 4-[(4-fluoro-2-methylbenzoyl)-                                           amino]-3-chlorobenzoate                                           513          Ethyl 4-[(5-fluoro-2-methylbenzoyl)-                                           amino]-3-chlorobenzoate                                           514          Ethyl 4-[[2-fluoro-5-(trifluoromethyl)-                                        benzoyl]amino]-3-chlorobenzoate                                   515          Ethyl 4-[[2-(trifluoromethyl)benzoyl]-                                         amino]-3-chlorobenzoate                                           516          Ethyl 4-[[3-(trifluoromethyl)benzoyl]-                                         amino]-3-chlorobenzoate                                           ______________________________________                                    

EXAMPLE 517

N-(4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)phenyl]-3-fluoro-2-methylbenzamide

A solution of 2.87 g of 3-fluoro-2-methylbenzoic acid in 25 ml of thionyl chloride is refluxed for 1.75 hour and the excess thionyl chloride removed under vacuum. To the residue is added toluene (several times) and the toluene removed under vacuum after each addition to give 3-fluoro-2-methylbenzoyl chloride.

To a solution of 0.25 g of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 0.0914 g of triethylamine in 6 ml of dichloromethane under argon is added a solution of 0.156 g of 3-fluoro-2-methylbenzoyl chloride in 1.5 ml of dichloromethane. The mixture is stirred overnight at room temperature and is washed with H₂ O and saturated NAHCO₃. The organic layer is treated with activated carbon and filtered through magnesium sulfate. The filtrate is evaporated, ethyl acetate added and the solvent removed to give 0.38 g of white crystals, m.p. 245-250° C.: Exact mass by mass spectrometry--441.1720(M+H).

EXAMPLE 518

N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide

A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with H₂ O, 1 N HCl, H₂ O, 1M NAHCO₃, brine and dried (Na₂ SO₄). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137-140° C.

EXAMPLE 519

N-[4-(4H-Pyrazolo[5,1- c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-2-methylbenzamide

As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.369 g of 4-[(2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature to give crystals (from ethyl acetate) m.p. 241-244° C.

EXAMPLE 520

N-[4-(4H-Pyrazolo[5,1-c][1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-2,4-dichlorobenzamide

As described for Example 518, a mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.472 g of 4-[(2,4-dichlorobenzoyl)amino]-benzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight to give the product (0.27 g) as a pale yellow glass; anal. calc'd: C, 58.7; H, 3.4; N, 11.0; Cl, 20.8 Found C, 57.3; H, 3.3; N, 9.5; Cl, 21.3.

EXAMPLE 521

5,10-Dihydro-5-(4-nitro-2-chlorobenzoyl)-4H)-pyrazolo[5,1-c][1,4]benzodiazepine

To a solution of 1.85 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine and 1.60 g of diisopropylethylamine in 50 ml of dichloromethane, cooled in an ice bath, is added dropwise a solution of 2.64 g of 4-nitro-2-chlorobenzoyl chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and poured into water. The organic layer is separated and washed with H₂ O, saturated NAHCO₃, H₂ O and dried (Na₂ SO₄). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is crystallized from dichloromethane-hexane to give 3.0 g of crystals, m.p. 197-199° C.

EXAMPLE 522

5,10-Dihydro-5-(4-amino-2-chlorobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine

A mixture of 0.553 g of 5,10-dihydro-5-(4-nitro-2-chlorobenzoyl)-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 1.70 g of stannous chloride dihydrate in 20 ml of ethanol is heated at 70-80 ° C for 1 hour. The mixture is chilled, made basic with 1 M NaHCO₃ and then stirred at room temperature for 0.5 hour. The mixture is brought to pH 5 with acetic acid and extracted (several times) with ethyl acetate. The combined extracts are dried (Na₂ SO₄) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated and the residue dissolved in dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 0.40 g of a glass, m.p. 98-117° C.; Anal. Calc'd: C, 62.9; H, 4.7; N, 16.3; Cl, 11.6. Found: C, 62.4; H, 4.3; N, 15.6; Cl, 11.7.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         523          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                       2-fluorobenzamide, m.p. 223-226° C.                        524          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                       2-(thiomethylbenzamide), white foam                               525          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                       2,3-dimethylbenzamide, m.p. 189-192° C.                    526          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                       2-chlorobenzamide, m.p. 198-203° C.                        527          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                       4-fluoro-2-chlorobenzamide, m.p.                                               139-141° C.                                                528          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                       2-(trifluoromethyl)benzamide, white foam                          529          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl]-3-chlorophenyl]-                                       2,6-dichlorobenzamide, m.p. 246-248° C.                    ______________________________________                                    

EXAMPLE 530

N -(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl -2-chlorophenyl]-2-methylbenzamide

To a mixture of 1.38 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.11 g of N,N-diopylethylamine in 50 ml of dichloromethane is 2.61 g of 4-[(2-methylbenzoyl)amino]-3-chlorobenzoyl chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and then washed with H₂ O and saturated NaHCO₃. The organic layer is dried (Na₂ SO₄) and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated, the residue (4.0 g) dissolved in dichloromethane and again filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated to give the product as a glass (3.62 g). A 1.8 g sample of the glass is crystallized from ethyl acetate to give 1.4 g of crystals, m.p. 176-178° C.

The following Examples are prepared using the conditions of Example 530.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         531          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,3-dimethylbenzamide                                             532          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,5-dimethylbenzamide                                             533          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,6-dimethylbenzamide                                             534          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-chlorobenzamide                                                 535          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,4-dichlorobenzamide                                             536          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,5-dichlorobenzamide                                             537          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       3,5-dichlorobenzamide                                             538          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                       3-fluorobenzamide, amorphous solid                                539          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-chloro-4-fluorobenzamide                                        540          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-methyl-4-chlorobenzamide                                        541          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-(methylthio)benzamide                                           542          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-chlorobenzeneacetamide                                          543          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-methylbenzeneacetamide                                          544          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-methylthiophene-3-carboxyamide                                  545          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       3-methylthiophene-2-carboxamide                                   546          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       3-fluoro-2-methylbenzamide, m.p. 230-                                          231° C.                                                    547          N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       5-fluoro-2-methylbenzamide, m.p. 178-                                          180° C.                                                    548          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,3-dichlorobenzamide                                             549          N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,3-difluorobenzamide                                             550          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       4-fluoro-2-methylbenzamide                                        551          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-methoxybenzamide                                                552          N-(4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-(trifluoromethoxy)benzamide                                     553          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-methoxy-4-chlorobenzamide                                       554          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-(trifluoromethyl)benzamide                                      555          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       3-(trifluoromethyl)benzamide                                      556          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,6-dichlorobenzamide                                             557          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,3,5-trichlorobenzamide                                          558          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-fluoro-5-(trifluoromethyl)benzamide                             559          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       4-fluoro-2-(trifluoromethyl)benzamide                             560          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2-fluoro-3-(trifluoromethyl)benzamide                             561          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-chlorophenyl]-                                       2,5-difluorobenzamide                                             562          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-5-fluoro-2-methylbenzamide                                563          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-2,3-dimethylbenzamide                                     564          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-3-fluoro-2-methylbenzamide                                565          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-2,4-dichlorobenzamide                                     566          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-2,3-dichlorobenzamide                                     567          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,3-dichloro-                                          phenyl]-2-methylbenzamide                                         568          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-5-fluoro-2-methylbenzamide                                569          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2,3-dimethylbenzamide                                     570          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-3-fluoro-2-methylbenzamide                                571          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2,4-dichlorobenzamide                                     572          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2,3-dichlorobenzamide                                     573          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2-methylbenzamide                                         574          N-[4-(5H-pyrrolo[2,1-c][1,4)benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2,3-dichlorobenzamide                                     575          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2,5-dichlorobenzamide                                     576          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2-(methylthio)benzamide                                   577          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2-chlorobenzamide                                         578          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2-(trifluoromethyl)benzamide                              579          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2,5-dichloro-                                          phenyl]-2-(trifluoromethoxy)benzamide                             ______________________________________                                    

EXAMPLE 580

2,4-Dichloro-N-[4-[(3-formyl-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H) -yl)carbonyl]phenyl]benzamide

To a solution of 0.48 g of 2,4-dichloro-N-[4-(5H[-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl)-carbonyl)phenyl]benzamide in 2 ml of N,N-dimethylformamide at 0° C. is slowly added 0.3 ml of POCl₃. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The final mixture is quenched with ice and made alkaline with 2 N NaOH to pH 12. The resulting precipitate is collected, washed with water and dried in vacuo to give 0.55 g of solid. Further washing with 1:2 ether-isopropanol gives 0.50 g of white solid. NS(CI) calculated 503.0774; found 503.0789.

EXAMPLE 581

2,4-Dichloro-N-(4-[[3-(hydroxymethyl)-5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]-phenyl]benzamide

To a suspension of 39 mg of NaBH in 1 ml of tetrahydrofuran is added 0.42 g of 2,4-dichloro-N-[4-[(3-formyl-5H-pyrrolo[2,1-a][1,4]benzodiazepin-10 (11H)-yl)carbonyl]phenyl]benzamide and the reaction mixture stirred at room temperature for 18 hours and then quenched with water. The tetrahydrofuran is evaporated in vacuo and the aqueous residue treated with 5 ml of 1 N NaOH and extracted with 50 ml of ethyl acetate. The organic extract is washed with brine, dried over Na₂ SO₄ and evaporated to give 0.47 g of a foam. Preparative thick layer chromatography by elution with 2:1 ethyl acetate-hexane gives 0.24 g of white solid. NS(FAB): 488(MH³⁰ -OH).

EXAMPLE 582

2,4-Dichloro-N-[4-[[3-(1H-imidazol-1-ylmethyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H )-yl]-carbonyl]phenyl]benzamide

To a suspension of 0.28 g of N,N-dimethylglycine hydrochloride in 5 ml of tetrahydrofuran is added 0.21 g of triethylamine and 0.35 g of carbonyldiimidazole. After stirring at room temperature for 30 minutes and then heating at reflux for 18 hours, the tetrahydrofuran is evaporated in vacuo to a residue which is dissolved in ethyl acetate and washed with water, saturated NaHCO₃ and brine and dried over Na₂ SO₄, filtered and evaporated in vacuo to a residue. The residue is washed with ether-hexanes (1:1) to give 0.17 g of white solid. MS(FAB): 556(M+H).

EXAMPLE 583

α-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

To a solution of 0.61 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.47 g of (+)-2-chloro-2-phenylacetyl chloride in 2 ml of methylene chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 10 ml of 50% NaHCO₃. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NAHCO₃ and brine and then dried with Na₂ SO₄ followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with etherhexane to give 0.98 g of pink solid. MS(CI): 456(M+H).

EXAMPLE 584

α-[[2-(Dimethylamino)ethyl]thio]-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzeneacetamide

A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzeneacetamide, 0.47 g of 2-dimethylaminoethanethiol hydrochloride in 2 ml of methyl alcohol, 0.30 g of triethylamine and 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is heated at 60° C. for 48 hours. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexane to give 0.15 g of beige solid. MS(CI): 525(M+H).

EXAMPLE 585

α-[N-(Acetamido)amino]-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A mixture of 0.14 g of α-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]benzeneacetamide, 0.17 g of glycinamide HCl, 0.15 g of triethylamine, 3 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1 ml of methyl alcohol is heated at 75° C. for 2 days. The methyl alcohol is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The solid is dissolved in ethyl acetate and washed with saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture is filtered and the filtrate evaporated in vacuo to a residue which is stirred with ether-hexanes to give 0.13 g of tan solid. MS(CI): 494(M+H).

EXAMPLE 586

α-(Dimethylamino)-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzene-acetamide

A partial solution of ??g of a-chloro-N-[4- (5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide in 1 ml of methanol is treated with 0.5 ml of dimethylamine and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and stirring continued for 20 hours. The methanol is evaporated and the residue diluted with water. The resulting solid is washed with water, dissolved in ethyl acetate and the organic layer washed with saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture is filtered and the filtrate evaporated in vacuo to give a residue which is stirred with ethyl acetate-hexane to give 0.15 g of a beige solid. MS(CI): 465(M+H).

EXAMPLE 587

α-(Acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-ylcarbonyl)phenyl]-benzeneacetamide

To a solution of 0.30 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added 0.15 g of triethylamine followed by 0.27 g of O-acetylmandelic acid chloride. The mixture is stirred at room temperature for 1 hour and then diluted with 50% NaHCO₃. The methylene chloride is evaporated and the residue is extracted with ethyl acetate. The separated organic layer is washed with saturated NaHCO₃ and brine and then dried with Na₂ SO₄ followed by filtering through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is stirred with etherhexane to give 0.54 g of beige solid. MS(CI): 480(M+H).

EXAMPLE 588

(±)α-Hydroxy-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide

A solution of 0.34 g of a-(acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide in 2 ml of 1 N NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30 minutes, diluted with 2 ml of water and evaporated in vacuo. The aqueous suspension is extracted with 30 ml of ethyl acetate and the extract washed with brine, dried with Na₂ SO₄ and filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to a residue. The residue is stirred with ether-hexanes to give 0.26 g of cream colored solid. MS(CI): 438(M+H).

EXAMPLE 589

2-Chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide

To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl) -5H-pyrrolo[2, 1-c][1,4]-benzodiazepine in 10 ml of methylene chloride is added 0.46 g of triethylamine and 36 mg of dimethylaminopyridine followed by the slow addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room temperature for 3 hours then partitioned with 10 ml of 50% NAHCO₃ and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, washed with 50% NaHCO₃, H₂ O, EtOAc (2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).

EXAMPLE 590

N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide

A stirred suspension of 0.19 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11)-ylcarbonyl)phenyl]acetamide in 1 ml of methylene chloride is added 0.44 g of morpholine followed by 1 ml of 1,3-di- methyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone and stirring continued for 20 hours. The methylene chloride is evaporated and the residue diluted with water. The resulting suspension is filtered and the precipitate washed with water. The brown solid is dissolved in 15 ml of ethyl acetate and washed with saturated NaHCO₃, brine and dried with Na₂ SO₄. The mixture is filtered and the filtrate evaporated in vacuo to give 0.23 g of a colorless gum which is stirred with ethyl acetate-hexanes to give 0.21 g of white solid. MS(CI): 431(M+H).

EXAMPLE 591

N-[(2-Chlorophenyl)methyl]-N-[4-(5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide

A mixture of 0.11 g of N-[4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-4-morpholineacetamide, 56 mg of O-chlorobenzyl bromide and 0.41 g of K₂ CO₃ in 5 ml of acetonitrile is heated at reflux for 18 hours. An additional 30 mg of O-chlorobenzyl bromide and 0.4 mmol of sodium hydride is added followed by heating for 24 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried with Na₂ SO₄ and evaporated to give 0.18 g of a residue which is purified by chromatography on silica gel with 1:1 ethyl acetate-methylene chloride to give 80 mg of off white solid. MS(CI): 555(M+H).

EXAMPLE 592

Ethyl 10-[4-[(2,4-dichlorobenzoyl)amino]-3-methyl-benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-3-carboxylate

To a solution of 0.30 g of ethyl 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated NaHCO₃ and dried with Na₂ SO₄. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174-184° C.

EXAMPLE 593

Methyl 10-[4-(2,4-dichlorobenzoyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 50 ml of absolute methyl alcohol is added 0.15 g of sodium metal. After complete solution, 1.0 g of N-[4-[[3-(trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-yl)]carbonyl]phenyl]-2,4-dichlorobenzamide is added and the reaction mixture stirred overnight at room temperature. Methylene chloride is added followed by Na₂ SO₄. The organic layer is filtered through hydrous magnesium silicate. Hexane is added at the boil to the filtrate to give 0.29 g of solid.

EXAMPLE 594

N-[4-[[3-(trifluoroacetyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-yl)]carbonyl]phenyl]-2-(trifluoromethyl)benzamide

To a solution of 1.0 g of N-[4-(5H-pyrrolo-[2,1-c][1,4]benzodiazepin-10(11H) -ylcarbonyl)phenyl]-2-(trifluoromethyl)benzamide in 10 ml of methylene chloride is added 1.0 ml of trifluoroacetic anhydride followed by stirring for 18 hours at room temperature. The reaction mixture is washed with saturated NaHCO₃ dried with Na₂ SO₄, filtered and hexane added at the boil to give a solid which is crystallized from methylene chloride-hexane to give 0.89 g of solid, m.p. 248-250° C.

EXAMPLE 595

N-[4-[[3-(Trifluoroacetyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-yl]carbonyl]-3-chlorophenyl]-2-methylbenzamide

To a solution of 0.30 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10 (11H) -ylcarbonyl) -3-chlorophenyl]-2-methylbenzamide in 25 ml of methylene chloride is added 0.5 ml of trifluoroacetic anhydride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with saturated NaHCO₃, dried with Na₂ SO₄, filtered through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 0.22 g of colorless solid. MS: M+551.

EXAMPLE 596

Ethyl 10-[4-[(2,4-dichlorobenzoyl)amino]benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylate

To 50 ml of absolute ethyl alcohol is added 0.30 g of sodium metal, followed by the addition of 2.0 g of N-[4-[[3-(trichloroacetyl) -5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)yl]carbonyl]phenyl]-2,4-dichlorobenzamide and the mixture is stirred for 18 hours at room temperature. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and washed with H₂ O. The organic layer is dried with Na₂ SO₄ and filtered through hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give a solid which is crystallized from methylene chloride-hexane to give 0.57 g of a solid. MS(M⁺):548.2.

EXAMPLE 597

N-[4-[[3-(Trichloroacetyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2-(trifluoromethyl)benzamide

To a stirred solution of 0.48 g of N-[4-(5H-pyrrolo [2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2-(trifluoromethyl)benzamide in 20 ml of methylene chloride is added 0.40 g of trichloroacetic anhydride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated NAHCO₃, dried over Na₂ SO₄ and passed through a pad of hydrous magnesium silicate. Hexane is added at the boil to give 0.37 g of solid, m.p. 219-221° C.

EXAMPLE 598

N-[4-[[3-(Trichloroacetyl)-5H-pyrrolo[2,1-][1,4]-benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2,4-dichlorobenzamide

To a stirred solution of 4.76 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide in 150 ml of methylene chloride is added 3.75 g of trichloroacetic anhydride followed by stirring for 18 hours. The reaction mixture is washed with water and saturated NAHCO₃, dried over Na₂ SO₄ and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 2.91 g of solid.

EXAMPLE 599

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2,3,5-trichlorobenzamide

As described for Example 8, 0.50 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine is reacted with 0.483 g of 2,3,5-trichlorobenzoyl chloride to give a glass which is crystallized from ethyl acetate to give 0.686 g of crystals, m.p. 231-234° C.

EXAMPLE 600

N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]tetrahydrofurane-2-carboxamide

As described for Example 8, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine is reacted with 0.267 g of tetrahydrofurane-2-carbonyl chloride to give a glass which is crystallized from ethyl acetate to give 0.22 g of crystals, m.p. 208-214° C.

The following Examples are prepared using conditions of Example 297 with the appropriately substituted aroyl chloride.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         601          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                         dichlorophenyl]-2,3-dimethylbenzamide                             602          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                         dichlorophenyl]-2-chlorobenzamide                                 603          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                         dichlorophenyl)-2,4-dichlorobenzamide                             604          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                         dichlorophenyl]-3,5-dichlorobenzamide                             605          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2,5-                                         dichlorophenyl]-2-methyl-4-chloro-                                             benzamide                                                         606          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-methoxybenzamide                                  607          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-(trifluoromethoxy)                                             benzamide                                                         608          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-(trifluoromethyl)                                              benzamide                                                         609          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2,4-dichlorobenzamide,                                           amorphous white solid, m.p. 134-137° C.                    610          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-(methylthio)benzamide                             611          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-3-fluoro-2-methyl-                                               benzamide, amorphous white solid,                                              m.p. 136-138° C.                                           612          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-5-fluoro-2-methyl-                                               benzamide, amorphous solid, m.p.                                               132-135° C.                                                613          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5-]benzodiazepin-5-yl)carbonyl]-3-                                          chlorophenyl]-4-fluoro-2-methyl-                                               benzamide                                                         614          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-4-fluoro-2-(trifluoro-                                           methyl)benzamide                                                  615          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2,3-dichlorobenzamide                               616          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2,3-difluorobenzamide                               617          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-fluoro-5-(trifluoro-                                           methyl)benzamide                                                  618          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-fluoro-3-(trifluoro-                                           methyl)benzamide                                                  619          N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl)-4-fluoro-2-(trifluoro-                                           methyl)benzamide                                                  620          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2,5-difluorobenzamide                               621          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2,3-difluorobenzamide                               622          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2, 5-dimethylbenzamide                              623          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-3-methyl-2-thiophene-                                            carboxamide                                                       624          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-methyl-3-thiophene-                                            carboxamide                                                       625          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-methyl-3-furane                                                carboxamide                                                       626          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-3-methyl-2-furane-                                               carboxamide                                                       627          N-[4-[(6,7-Dihydro-5H-pyrrolo(1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-chlorobenzeneacetamide                            628          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-2-methylbenzeneacetamide                            629          N-(4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           chlorophenyl]-4-fluoro-3-(trifluoro-                                           methyl)benzamide                                                  630          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-3-fluoro-2-methyl-                                               benzamide                                                         631          N-[4-(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                           [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,3-dichlorobenzamide                               632          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,3-difluorobenzamide                               633          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-4-fluoro-2-methyl-                                               benzamide                                                         634          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-4-yl)carbonyl]-2-                                           chlorophenyl]-5-fluoro-2-methyl-                                               benzamide                                                         635          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-fluoro-5-(trifluoro-                                           methyl)benzamide                                                  636          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-methylbenzamide                                   637          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-chlorobenzamide                                   638          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,3-dimethylbenzamide                               639          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,5-dimethylbenzamide                               640          N-[4-[(6,7-Dihydro-5H-pyrolo[1,2-a]-                                           [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-methoxybenzamide                                  641          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-(trifluoromethoxy)-                                            benzamide                                                         642          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-methoxy-4-chloro-                                              benzamide                                                         643          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,6-dichlorobenzamide                               644          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-(methylthio)benzamide                             645          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2-(trifluoromethyl)-                                             benzamide                                                         646          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-3-(trifluoromethyl)-                                             benzamide                                                         647          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           chlorophenyl]-2,3,5-trichlorobenzamide                            648          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-3-fluoro-2-methylbenz-                                          amide                                                             649          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-5-fluoro-2-methylbenz-                                          amide                                                             650          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-4-fluoro-2-methylbenz-                                          amide                                                             651          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-2,4-dichlorobenzamide                              652          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-2,3-dimethylbenzamide                              653          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-3-                                           methoxyphenyl]-3-fluoro-5-(trifluoro-                                          methyl)benzamide                                                  654          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl]-3-fluoro-2-methylbenz                                           amide                                                             655          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl]-5-fluoro-2-methylbenz-                                          amide                                                             656          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl)-4-fluoro-2-methylbenz-                                          amide                                                             657          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl]-2,4-dichlorobenzamide                              658          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl]-2,3-dimethylbenzamide                              659          N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a]-                                          [1,5]benzodiazepin-5-yl)carbonyl]-2-                                           methoxyphenyl]-3-fluoro-5-(trifluoro-                                          methyl)benzamide                                                  ______________________________________                                    

EXAMPLE 660

N-[4-[[[3-[-[(Dimethylamino)methyl]-5H-pyrrolo[2,1-c]-[1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2-methylbenzamide

To a stirred solution of 0.842 g of 2-methyl-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl-carbonyl)phenyl]benzamide in 25 ml of 1:1 methanoltetrahydrofuran is added 10 ml of 35% formaldehyde and 10 ml of 30% N,N-dimethylamine at 0° C. After 2 drops of acetic acid is added, the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in chloroform and washed with water. The organic layer is dried with Na₂ SO₄ and evaporated in vacuo to a residue. The residue is chromatographed on silica gel with 10:1 ethyl acetate-methanol as eluent to give 0.800 g of the desired product, M⁺ H:479.

The following products are prepared by using the condition of Example 660 and by using the appropriately substituted benzamide.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         661          N-[4-[[3-(1-piperidinylmethyl)-5H-                                             pyrrolo[2,1-c][1,4]benzodiazepin-                                              10(11H-yl]carbonyl]phenyhl]-2-methyl-                                          benzamide, solid; mass spectrum (M.sup.+ H)                                    518                                                               662          N-[4-[[3-(4-morpholinomethyl)-5H-                                              pyrrolo[2,1-c][1,4]benzodiazepin-                                              10(11H)-yl]carbonyl]phenyl]-2-methyl-                                          benzamide, solid; mass spectrum (M.sup.+ H)                                    521                                                               663          N-[4-[[3-[[4-(phenylmethyl)-1-pipera-                                          zinyl]methyl]-5H-pyrrolo[2,1-c][1,4]-                                          benzodiazepin-10(11H)-yl]carbonyl]-                                            phenyl]-2-methylbenzamide, solid; mass                                         spectrum (M.sup.+ H) 610                                          664          N-[4-[[3-[(dimethylaminomethyl)-                                               5H-pyrrolo[2,1-c][1,4]benzodiazepin-                                           10(11H)-yl]carbonyl]phenyl]-2,4-di-                                            chlorobenzamide, solid; mass spectrum                                          (M.sup.+ H) 535                                                   665          N0[4-[[3-(1-pyrrolidinylmethyl)-                                               5H-pyrrolo[2,1-c][1,4]benzodiazepin-                                           10(11H)-yl]carbonyl]phenyl]-2,4-di-                                            chlorobenzamide, solid; mass spectrum                                          (M.sup.+ H) 561                                                   666          N-[4-[[3-(4-morpholinomethyl)-5H-                                              pyrrolo[2,1-c][1,4]benzodiazepin-                                              10(11H)-yl]carbonyl]phenyl]-2,4-di-                                            chlorobenzamide, solid; mass spectrum                                          (M.sup.+ H) 576                                                   667          N-[4-[[3-[(diethylamino)methyl]-5H-                                            pyrrolo[2,1-c [1,4]benzodiazepin-                                              10(11H)-yl]carbonyl]phenyl]-2,4-di-                                            chlorobenzamid,e solid; mass spectrum                                          (M.sup.+ H) 562                                                   668          N-[4-[[3-[(dimethylamino)methyl]-5H-                                           pyrrolo[2,1-c][1,4]benzodiazpein-                                              10(11H)-yl]carbonyl]-3-chlorophenyl]-                                          5-fluoro-2-methylbenzamide, solid;                                             mass spectrum (M.sup.+ H) 531                                     669          N-[4-[[3-[(dimethylamino)methyl]-5H-                                           pyrrolo[2,1-c][1,4]benzodiazepin-                                              10(11H)-yl]carbonyl]-3-chlorophenyl]-                                          2-methylbenzamide, solid; mass spectrum                                        (M.sup.+ H) 513                                                   ______________________________________                                    

EXAMPLE 670

N-[4-[(3-Acetyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl]phenyl]-2,4-dichlorobenzamide

A stirred solution of 0.954 g of N-[4-(5H-pyrrolo(2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)-phenyl]-2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride is heated at reflux for 24 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetatehexane (7:3) to give 0.800 g of a white solid; mass spectrum (M⁺ H)519.

EXAMPLE 671

1-[2-Nitro-5-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde

To a stirred slurry of 2.2 g of sodium hydride (60% in oil, washed with hexane) in tetrahydrofuran is added at 0° C a solution of 4.5 g of pyrrole-2-carboxaldehyde in 25 ml of tetrahydrofuran. After the addition is complete, a solution of 15 g of ethyl 4-nitro-3-bromomethylbenzoate in 30 ml of dry tetrahydrofuran is slowly added under nitrogen. The reaction mixture is stirred at 20° C. for 8 hours and carefully quenched with water. The reaction mixture is extracted with chloroform which is washed with water, dried with Na₂ SO₄ and concentrated in vacuo to give 12 g of the desired product as a solid; mass spectrum (M⁺ H)349.

EXAMPLE 672

1-[2-Nitro-4-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde

The conditions of Example 671 are used with ethyl 3-nitro-4-bromomethylbenzoate to give 13.0 g of the desired product as a solid; mass spectrum (M⁺ H)349.

EXAMPLE 673

Ethyl 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-7-carboxylate

A solution of 10.0 g of 1-[2-nitro-5-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde in 150 ml of absolute ethanol containing 1.0 g of 10% Pd/c is hydrogenated in a Parr apparatus for 16 hours under 40 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to a residue of 5.5 g of the desired product as a solid; mass spectrum (M⁺ H)255.

EXAMPLE 674

Ethyl 10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-8-carboxylate

The hydrogenation conditions of Example 673 are used with 1-[2-nitro-4-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde to give 5.0 g of the desired product as a solid; mass spectrum (M⁺ H)255.

EXAMPLE 675

Ethyl 10,11-Dihydro-10-[4-[(2-methylbenzoyl)amino]-benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate

A solution of 1.2 g of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-7-carboxylate in 100 ml of methylene chloride is cooled to 0° C. and 10 ml of triethylamine added followed by 1.5 g of 4-[(2-methylbenzoyl)amino)benzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and concentrated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na₂ SO₄ and concentrated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 40% ethyl acetatehexane to give 1.0 g of the desired product as a solid; mass spectrum (M⁺ H)494.

EXAMPLE 676

Ethyl 10,11-Dihydro-10-[4-[(2-methylbenzoyl)amino]-benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8-carboxylate

The conditions of Example 675 are used with ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylate to give 1.2 g of the desired product as a solid; mass spectrum (M⁺ H)494.

The subject compounds of the present invention are tested for biological activity as follows:

EXAMPLE 677

10,11-Dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c]-[1,4]benzodiazepine

A 292 mg sample of sodium hydride in oil is washed, under argon, with pentane. The residue is diluted with 17 ml of dioxane and then 1.35 g of 10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine is added. The reaction mixture is warmed slightly until the hydrogen evolution ceases. To the cooled reaction mixture is added a solution of 1.36 g of p-nitrobenzoyl chloride in 45 ml of dioxane and the mixture is stirred at room temperature for 18 hours. The solvent is evaporated in vacuo and the residue is heated with CHCl₃, filtered hot and the filter cake washed with hot CHCl₃. The combined CHCl₃ layers are washed with water, saturated NAHCO₃, treated with activated charcoal, filtered through a pad of MgSO₄ and the filtrate evaporated in vacuo to give 1.82 g of brown solid residue. The residue is purified by flash chromatography by elution with CHCl₃ --MeOH to give 630 mg of the desired product as a solid. HR FABMS:(M+H)=335.3433.

EXAMPLE 678 10,11-Dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c]-[1.4]benzodiazepine

A mixture of 0.550 g of 10,11-dihydro-10-(4-nitrobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine and 1.86 g of SnCl₂.2H₂ O in 22 ml of ethyl alcohol is refluxed for 1 hour under argon. The mixture is diluted with water and then a solution of 10% NaHCO₃ is added until the reaction mixture is basic. Additional ethyl alcohol is added and reaction mixture evaporated in vacuo to give a residue which is triturated with 1:1 CHCl₃ --CH₃ OH several times and filtered. The filtrates are combined, treated with activated carbon and filtered through diatomaceous earth. The filtrate is evaporated in vacuo to give 680 mg of tan crystalline solid. The solid is stirred in ethanol, water and 10% NaHCO₃ to pH=8, for 5 hours and extracted with CHCl₃ three times. The combined extracts are treated with activated carbon, filtered through MgSO₄ and evaporated in vacuo to give 370 mg of tan crystalline solid. CIMS(CH₄):MH⁺ =305.

EXAMPLE 679 N-[4-(5H-Imidazo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide

A slurry of 0.330 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-imidazo[2,1-c][1,4]benzodiazepine in 15 ml of dioxane is stirred and warmed slightly to obtain a nearly complete solution. The reaction mixture is cooled to room temperature and 43 mg of sodium hydride in oil added. The mixture is warmed slightly. Gas evolution stops in a few minutes. The reaction mixture is cooled to room temperature and 153 μl of 2,4-dichlorobenzoyl chloride in 2.5 ml of dioxane added. An additional 3.5 ml of dioxane is added and the reaction mixture stirred at room temperature for 2 days. The volatiles are evaporated la vacuo to a residue which is partitioned between water and chloroform. The organic layer is separated and the aqueous phase extracted with chloroform two more times. The combined organic layers are trated with activated carbon and filtered through MgSO₄. The filtrate is evaporated in vacuo to a tan foam which is purified by flash chromatography on silica gel by elution with CHCl₃ and 3-7% CH₃ OH in chloroform to give 310 mg of tan foam.

EXAMPLE 680 6,7-Dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine

To a solution of 0.28 g of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 6 ml of methylene chloride is added 0.30 g of triethylamine followed by 0.50 g of 2-chloro-4-nitrobenzoyl chloride in 0.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour then quenched with 5 ml of saturated NaHCO₃. The methylene chloride is evaporated in vacuo and the residue is diluted with 5 ml of water and extracted with 20 ml of ethyl acetate. The organic layer is separated, washed with saturated NAHCO₃ and brine, dried with Na₂ SO₄ and evaporated in vacuo to give 0.59 g of a yellow foam which is triturated with ether-hexanes to give 0.56 g of the desired product as off-white solid. MS(CI): 368(M+H)(Cl³⁵); 370(M+H)(Cl³⁷).

EXAMPLE 681 6,7-Dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine

To a solution of 0.50 g of 6,7-dihydro-5-(2-chloro-4-nitrobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 10 ml of ethyl alcohol and 2 ml of tetrahydrofuran is added 2.35 g of SnCl₂.2H₂ O and the mixture stirred at 55° C. for 30 minutes. The solvents are evaporated in vacuo to a residue which is stirred with 20 ml of 1 N NaOH and 40 ml of ethyl acetate for 15 minutes and filtered through diatomaceous earth. The filter pad is washed with 2×10 ml of ethyl acetate and the combined extracts washed with brine, dried (Na₂ SO₄) and evaporated in vacuo to give 0.47 g of solid residue which is triturated with ether-hexane to give 0.43 g of light yellow crystalline solid. Ms(CI): 338(M+H, Cl³⁵); 340(M+H, Cl³⁷).

EXAMPLE 682 N-[4-[(6,7-Dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl)carbonyl]-3-chlorophenyl]-3-fluoro-2-methylbenzamide

To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo-[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.08 g of 3-fluoro-2-methylbenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred for 2 hours at room temperature and then 2 ml of 1 NaOH added. The volatiles are evaporated under vacuum and the residue dissolved in 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred for 2 hours and evaporated and the residue diluted with 2 ml of 1 N NaOH and 5 ml of water. The mixture is extracted with ethyl acetate (15 ml) and the extract washed with brine and dried (Na₂ SO₄). The solvent is removed and the residue triturated with diethyl ether-hexane to give 0.15 g of white solid: Mass Spectrum (CI)474(M+H, Cl³⁵); 476(M+H, Cl³⁷).

EXAMPLE 683 N-[4-[(6,7-Dihydro-5H[-pyrrolo[1,2-a][1,5]benzodiazepin-5-yl) carbonyl]-3-chlorophenyl]-2,4dichlorobenzamide

To a mixture of 0.10 g of 6,7-dihydro-5-(4-amino-2-chlorobenzoyl)-5H-pyrrolo[1,2-a][1,5]benzodiazepine and 0.06 g of triethylamine in 6 ml of dichloromethane is added 0.10 g of 2,4-dichlorobenzoyl chloride in 0.5 ml of dichloromethane. The mixture is stirred at room temperature for 2 hours and 2 ml of 1 N NaOH is added. The volatiles are removed under vacuum and to the residue is added 2 ml of tetrahydrofuran and 1 ml of methanol. The mixture is stirred at room temperature for 2 hours and the volatiles removed. To the residue is added 2 ml of 1 N NaOH and 5 ml of H₂ O. The mixture is extracted with ethyl acetate and the extract washed with brine and dried (Na₂ SO₄). The solvent is removed and the solid triturated with diethyl ether-hexane to give 0.15 g of white solid, Mass Spectrum (CI): 510(M+H, Cl³⁵).

EXAMPLE 684 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(1H-[1,2,4]-triazol-1-yl)-acetamide

To a suspension of 0.20 g of 1,2,4-triazole sodium in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is added 0.10 g of 2-chloro-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide in 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone followed by stirring at room temperature for 3 hours. The reaction mixture is quenched with 15 ml of water and the resulting solid is collected, washed with water and hexanes to give 70 mg of the desired product as a tan solid. MS(CI): 413(M+H).

EXAMPLE 685 N-[4-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-(2-formyl-1-pyrrolo)acetamide

To a suspension of 72 mg of sodium hydride (60% in oil) in 5 ml of tetrahydrofuran is added 0.14 g of pyrrole-2-carboxaldehyde. The mixture is stirred for 1 hour at room temperature and 94 mg of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 0.19 g of 2-chloro-N-[4-(5,H-pyrrolo[2,1-c)][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]acetamide added. The mixture is stirred at room temperature, water added and the tetrahydrofuran evaporated in vacuo. The resulting suspension is filtered and the precipitate washed with water and hexanes. The collected solid is purified by column chromatography on silica gel by elution with 3:2 ethyl acetate-hexanes to give 50 mg of pink solid. MS(CI): 439(M+H).

EXAMPLE 686 N-[4-(3-Chloro-4H-pyrazolo[5,1-c][1,4]benzodiazepin-5-(10H)-ylcarbonyl)phenyl]-2-methyl-5-fluorobenzamide

A mixture of 356 mg of N-[4H-pyrazolo[5,1-c]-[1,4]benzodiazepin-5(10H)-ylcarbonyl)-3-chlorophenyl]-5-fluoro-2-methylbenzamide and 122 mg of N-chlorosuccinimide in 5 ml of methylene chloride is refluxed on a steam bath for 3 hours. The reaction mixture is washed with saturated NaHCO₃, H₂ O and brine, then dried over Na₂ SO₄ and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 190 mg of the desired product as a solid.

The following examples are prepared using the conditions of Example 465.

    ______________________________________                                         Example No.  Compound                                                          ______________________________________                                         687          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-bromo-                                        benzamide, white solid                                            688          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-                                              (acetoxy)benzamide, light yellow solid                            689          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-                                              hydroxybenzamide, light yellow solid                              690          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-1-                                              naphthylcarboxamide, white solid                                  691          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-methylphenyl]-                                       2-methylbenzamide, amorphous solid                                692          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                       4-fluorobenzamide, white foam                                     693          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-(tri-                                         fluoromethyl)-4-fluorobenzamide, white                                         solid                                                             694          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-methylphenyl]-                                       5-fluoro-2-methylbenzamide, m.p. 180-                                          182° C.                                                    695          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-methoxy-                                             phenyl]-5-fluoro-2-methylbenzamide,                                            amorphous solid                                                   696          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-fluoro-4-(trifluoromethyl)                                           benzamide, m.p. 140-154° C.                                697          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-methylbenzeneacetamide,                                              white glass                                                       698          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-fluoro-6-(trifluoromethyl)                                           benzamide, white solid, m.p. 150-230° C.                   699          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-fluoro-3-(trifluoromethyl)                                           benzamide, white glasS                                            700          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-chloro-5-(methylthio)                                                benzamide, white crystals, m.p.                                                124-134° C.                                                701          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2,5-dimethylbenzamide,                                                 crystalline solid, m.p. 253-255° C.                        702          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chloro-                                              phenyl]-2-chloro-3,4-dimethoxybenzamide,                                       yellow foam                                                       703          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-6-chloro-3-                                            methoxyphenyl]-2-methylbenzamide,                                              crystals, m.p. 214-215° C.                                 704          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-2-methoxy                                              phenyl]-2,5-dimethlbenzamide,                                                  crystals, m.p. 174-175° C.                                 705          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2-chloro-                                       3,4-dimethoxybenzamide, white crystals,                                        m.p. 242-244° C.                                           706          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)phenyl]-2,5-                                            dimethylbenzamide, crystals,                                                   m.p. 158-160° C.                                           707          N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiaze-                                        pin-10(11H)-ylcarbonyl)-3-chlorophenyl]-                                       2-(trifluoromethyl)-4-fluorobenzamide,                                         white glass                                                       ______________________________________                                    

EXAMPLE 708 Methyl 4-[2-(2-chlorophenyl]-2-cyano-2-(4-morpholinyl)-ethyl]benzoate

A 0.876 g sample of 60% sodium hydride in oil is washed with hexane followed by the addition of 60 ml of dry N,N-dimethylformamide. The reaction mixture is stirred for 1 hour under argon at room temperature after the addition of 4.73 g of α-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture is added 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continued for 3 hours. Several drops of acetic acid is added to ice water and the reaction quenched. The pH is 3-4 and saturated NaHCO₃ added to adjust the pH to 6-7. Upon cooling a solid forms which is filtered, washed with water and dried to give 5.92 g of yellow solid. Crystallization from methylene chloride-hexane gives 2.10 g of the desired product as a crystalline solid, m.p. 116-118° C.

EXAMPLE 709 Methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate

A mixture of 1.0 g of methyl [4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate and 14 ml of water is heated at reflux for 20 minutes then poured over crushed ice. After stirring for 15 minutes the resulting solid is collected, washed with water and air dried to give 0.63 g of tan solid, m.p. 40-42° C.

EXAMPLE 710 4-[2-(2-Chlorophenyl)-2-oxoethyl]benzoic acid

A mixture of 18.78 g of methyl 4-[2-(2-chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of CH₃ OH, 72.2 ml of water and 5.2 g of NaOH is refluxed for 3 hours then acidified with 2 N citric acid. The reaction mixture is evaporated in vacuo to remove the CH₃ OH. The aqueous phase is extracted with CH₂ Cl₂ and acidified with 1 N HCl. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172° C.

EXAMPLE 711 3-Methoxy-4-nitrobenzoyl chloride

A stirred suspension of 1.0 g of 3-methoxy-4-nitrobenzoic acid and 1.40 ml of thionyl chloride is heated to reflux for 2 hours. The mixture is cooled to room temperature, 2 ml of iso-octane added and the mixture evaporated in vacuo to a solid residue. The residue is washed with iso-octane (2×2 ml), dried in vacuo to give 1.08 g of cream colored solid.

EXAMPLE 712 10,11-Dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a solution of 0.55 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 8 ml of methylene chloride is added 0.55 g of triethylamine followed by 0.97 g of 3-methoxy-4-nitrobenzoyl chloride. The reaction mixture is stirred at room temperature for 2 hours and then quenched with 10 ml of 1 N NaOH. The methylene chloride layer is evaporated and the resulting suspension filtered. The precipitate is washed with 1 N NaOH (2×5 ml), water (3×5 ml) and hexane (2×5 ml). The collected solid is dried in vacuo to give 1.13 g of off-white solid. MS(CI): 364(M+H).

EXAMPLE 713 10,11-Dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine

A mixture of 0.91 g of 10,11-dihydro-10-(4-nitro-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 4.51 g of SnCl₂.2H₂ O, 6 ml of ethyl alcohol, 6 ml of tetrahydrofuran and 16 ml of methylene chloride is stirred at 50° C. for 2 hours. The solvents are evaporated in vacuo and the residue dissolved in 80 ml of ethyl acetate. The solution is treated with 50 ml of 1 N NaOH with stirring for 30 minutes. The resulting suspension is filtered through diatomaceous earth. The pad is washed with ethyl acetate (3×15 ml). The combined ethyl acetate solutions are washed with brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate and evaporated in vacuo to 0.99 g of residue which is stirred with ether-hexanes to give 0.90 g of cream colored solid. MS(CI): 334(M+H).

EXAMPLE 714 10,11-Dihydro-10-[4-[(3-methylpropyloxycarbonyl)-amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.15 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.10 g of isobutylchloroformate. The reaction mixture is stirred for 3 hours and then quenched with 1 N NaOH. The organic layer is evaporated in vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate and evaporated in vacuo to give a residue which is stirred with ethyl acetate-methylene chloride to give 0.22 g of cream colored solid. MS(CI): 404(M+H).

EXAMPLE 715 10,11-Dihydro-10-[4-(pentanoyl)aminobenzoyl)]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.15 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 2 ml of methylene chloride is added 0.10 g of triethylamine followed by 0.09 g of valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched with 4 ml of 1 N NaOH. The methylene chloride is evaporated in vacuo and the residue dissolved in 5 ml of tetrahydrofuran for 1 hour and evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine and the organic layer dried (Na₂ SO₄), filtered through hydrous magnesium silicate, and evaporated in vacuo to give 0.23 g of a residue which is stirred with ether-hexanes to give 0.19 g of a white solid. MS(CI): 388(M+H).

EXAMPLE 716 10,11-Dihydro-10-[4-[(3-methylbutanoyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 1 ml of methylene chloride is added 0.06 g of triethylamine followed by 0.05 g of iso-valeryl chloride. The reaction mixture is stirred for 3 hours and then quenched with 1 N NaOH. The organic layer is evaporated in vacuo to a residue which is stirred in 5 ml of tetrahydrofuran for 1 hour, then evaporated in vacuo to a residue. The residue is extracted with ethyl acetate-methylene chloride, washed with brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate and evaporated in vacuo to give 0.15 g of residue which is stirred with ether-hexane to give 0.13 g of light yellow solid. MS(CI): 418(M+H).

EXAMPLE 717 10,11-Dihydro-10-[3-methoxy-4-[(butylsulfonyl)amino]benzoyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepine

To a stirred solution of 0.10 g of 10,11-dihydro-10-(4-amino-3-methoxybenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 2 ml of methylene chloride is added 60 mg of triethylamine followed by a solution of 56 mg of n-butylsulfonyl chloride in 0.5 ml of methylene chloride. After stirring at room temperature for 2 hours, the reaction mixture is evaporated in vacuo to a residue which is dissolved in methyl alcohol, stirred for 1 hour and evaporated in vacuo to a residue which is treated with 2 ml of NH₄ Cl and extracted with 15 ml of ethyl acetate. The organic extract is washed with saturated NaHCO₃, brine, dried (Na₂ SO₄), filtered through hydrous magnesium silicate and the filtrate evaporated to a residue. The residue is stirred with ether-hexanes to give 0.14 g of light yellow solid. MS(CI): 454(M+H).

Utility Testing

Binding Assay to Rat Hepatic V₁ Receptors

Rat liver plasma membranes expressing the vasopressin V₁ receptor subtypes are isolated by sucrose density gradient according to the method described by Lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at -70° C. until used in subsequent binding experiments.

For binding experiments, the following is added to the wells of a ninety-six well format microtiter plate: 100 μl of 100.0 mM Tris.HCl buffer containing 10.0 mM MgCl₂, 0.2% heat inactivated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 μl of [phenylalanyl-3,4,5,-³ H]vasopressin (S.A. 45.1 Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 μl of tissue membranes containing 20 μg of tissue protein. The plates are kept undisturbed on the bench top at room temperature for 120 min. to reach equilibrium. Non-specific samples are assayed in the presence of 0.1 μM of the unlabeled antagonist phenylalanylvasopressin, added in 20.0 μl volume.

For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, Md.). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC₅₀ values by the LUNDON-2 program for competition (LUNDON SOFTWARE, Ohio).

Binding Assay to Rat Kidney Medullary V₂ Receptors

Medullary tissues from rat kidneys are dissected out, cut into small pieces and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA with many changes of the liquid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate is filtered through several layers (4 layers) of cheese cloth. The filtrate is rehomogenized using a dounce homogenizer, with a tight fitting pestle. The final homogenate is centrifuged at 1500×g for 15 min. The nuclear pellet is discarded and the supernatant fluid recentrifuged at 40,000×g for 30 min. The resulting pellet formed contains a dark inner part with the exterior, slightly pink. The pink outer part is suspended in a small amount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry's method (Lowry et al., J. Biol. Chem., 1953). The membrane suspension is stored at -70° C., in 50.0 mM Tris.HCl, containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0 mg protein per ml of suspension until use in subsequent binding experiments.

For binding experiments, the following is added in μl volume to wells of a 96 well format of a microtiter plate: 100.0 μl of 100.0 MM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixture of protease inhibitors: leupeptin, 1.0 mg %; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 μl of [³ H] Arginine 8, vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 μl of tissue membranes (200.0 μg tissue protein). The plates are left undisturbed on the bench top for 120 min to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μl volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, Md.). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC₅₀ values by the LUNDON-2 program for competition (LUNDON SOFTWARE, Ohio). The results of this test on representative compounds of this invention are shown in Table XIII.

Radioligand Binding Experiments with Human Platelet Membranes

(a) Platelet Membrane Preparation

Frozen platelet rich plasma (PRP), (Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, N.Y.) are thawed to room temperature. The tubes containing the PRP are centrifuged at 16,000×g for 10 min. at 4° C. and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 mM Tris.HCl, pH 7.5 containing 120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000×g for 10 min. This washing step is repeated one more time. The wash discarded and the lysed pellets homogenized in low ionic strength buffer of Tris.HCl, 5.0 mM, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000×g for 10 min. The resulting pellet is resuspended in Tris.HCl buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000×g for 10 min. The final pellet is resuspended in 50.0 mM Tris.HCl buffer pH 7.4 containing 120 mM NaCl and 5.0 mM KCl to give 1.0-2.0 mg protein per ml of suspension.

(b) Binding to Vasopressin V₁ Receptor Subtype in Human Platelet Membranes

In wells of a 96 well format microtiter plate, add 100 μl of 50.0 mM Tris.HCl buffer containing 0.2% BSA and a mixture of protease inhibitors (aprotinin, leupeptin etc.). Then add 20 μl of [³ H]Ligand (Manning or Arg⁷ Vasopressin), to give final concentrations ranging from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 μl of platelet suspension (approx. 100 μg protein). Mix all reagents by pipetting the mixture up and down a few times. Non specific binding is measured in the presence of 1.0 μM of unlabeled ligand (Manning or Arg⁸ Vasopressin). Let the mixture stand undisturbed at room temperature for ninety (90) min. Upon this time, rapidly filter off the incubate under vacuum suction over GF/B filters, using a Brandel Harvester. Determine the radioactivity caught on the filter disks by the addition of liquid scintillant and counting in a liquid scintillator.

Binding to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfected with the cDNA Expressing the Human V₂ Vasopressin Receptor

(a) Membrane Preparation

Flasks of 175 ml capacity, containing attached cells grown to confluence, are cleared of culture medium by aspiration. The flasks containing the attached cells are rinsed with 2×5 ml of phosphate buffered saline (PBS) and the liquid aspirated off each time. Finally, 5 ml of an enzyme free dissociation Hank's based solution (Specialty Media, Inc., Lafayette, N.J.) is added and the flasks are left undisturbed for 2 min. The content of all flasks is poured into a centrifuge tube and the cells pelleted at 300×g for 15 min. The Hank's based solution is aspirated off and the cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500×g for 10 min to remove ghost membranes. The supernatant fluid is centrifuged at 100,000×g for 60 min to pellet the receptor protein. Upon completion, the pellet is resuspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml of suspension.

(b) Receptor Binding

For binding experiments, the following is added in μl volume to wells of a 96 well format of a microtiter plate: 100.0 μl of 100.0 μM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl₂ and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg %; 1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF., 20.0 μl of [³ H] Arginine⁸, vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 μl of tissue membranes (200.0 μg tissue protein). The plates are left undisturbed on the bench top for 120 min to reach equilibrium. Non specific binding is assessed in the presence of 1.0 μM of unlabeled ligand, added in 20 μl volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 μl volume to a final incubation volume of 200 μl. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, Md.). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC₅₀ values by the LUNDON-2 program for competition (LUNDON SOFTWARE, Ohio).

                                      TABLE XIII                                   __________________________________________________________________________     Binding Assay to Rat Hepatis V.sub.1 Receptors and Rat Kidney                  Medullary V.sub.2 Receptors or *Binding to V.sub.1 Receptor Subtype in         Human                                                                          Platelet and **Binding to Membranes of Mouse Fibroblast                        Cell Line (LV-2) Transfected with the cDNA Expressing the                      Human V.sub.2 Receptor                                                                                             V.sub.1                                                                               V.sub.2                             Ex. No.                                                                            Structure                       IC.sub.50 (μM)                                                                     IC.sub.50 (μM)                   __________________________________________________________________________         1 #STR154##                     0.097  0.029                               215                                                                                2 #STR155##                     0.016  0.022                               3                                                                                  3 #STR156##                     0.038  0.004                               4                                                                                  4 #STR157##                     0.12   0.014                               5                                                                                  5 #STR158##                     0.015  0.025                               6                                                                                  6 #STR159##                     0.023  0.003                               7                                                                                  7 #STR160##                     0.01   0.005                               8                                                                                  8 #STR161##                     0.056  0.035                               14                                                                                 9 #STR162##                     0.17   0.066                               40                                                                                 0 #STR163##                     2.4    0.12                                41                                                                                 1 #STR164##                     0.037  0.017                               82                                                                                 2 #STR165##                     (10 μM) 23%                                                                        (10 μM) 71%                      84                                                                                 3 #STR166##                     0.045  0.077                               85                                                                                 4 #STR167##                     0.009  0.013                               87                                                                                 5 #STR168##                     (10 μM) 63%                                                                        (10 μM) 30%                      89                                                                                 6 #STR169##                     0.023  0.008                               91                                                                                 7 #STR170##                     0.025  0.022                               93                                                                                 8 #STR171##                     0.0009 0.0007                              96                                                                                 9 #STR172##                     0.056  0.011                               116                                                                                0 #STR173##                     0.23   0.055                               117                                                                                1 #STR174##                     2.77   0.377                               354                                                                                2 #STR175##                     0.012  0.007                               355                                                                                3 #STR176##                     0.0165 0.35                                356                                                                                4 #STR177##                     0.037  0.053                               357                                                                                5 #STR178##                     0.019  0.017                               358                                                                                6 #STR179##                     0.011  0.016                               384                                                                                7 #STR180##                     0.188  0.059                               2                                                                                  8 #STR181##                     0.031  0.014                               9                                                                                  9 #STR182##                     0.007  0.004                               17 150                                                                             0 #STR183##                     1.2    0.11                                21                                                                                 1 #STR184##                     0.93   0.087                               36 179                                                                             2 #STR185##                     0.10   0.054                               54                                                                                 3 #STR186##                     0.31*  0.007**                             99                                                                                 4 #STR187##                     0.027  0.010                               210 214                                                                            5 #STR188##                     0.058  0.016                               217                                                                                6 #STR189##                     0.068 0.19*                                                                           0.005 0.01**                        267 271                                                                            7 #STR190##                     0.22   0.028                               274                                                                                8 #STR191##                     0.24*  0.031**                             297 298                                                                            9 #STR192##                     0.27   0.033                               465                                                                                0 #STR193##                     0.020* 0.0015**                            466                                                                                1 #STR194##                     0.026  0.004                               467                                                                                2 #STR195##                     0.031  0.005                               468                                                                                3 #STR196##                     0.027  0.029                               469                                                                                4 #STR197##                     0.094  0.015                               470                                                                                5 #STR198##                     0.054  0.0045                              471                                                                                6 #STR199##                     0.045  0.0083                              472                                                                                7 #STR200##                     0.89   (10 μM) 22%                      473                                                                                8 #STR201##                     (10 μM) 90%                                                                        (10 μM) 56%                      474                                                                                9 #STR202##                     0.087  0.035                               476                                                                                0 #STR203##                     0.084  0.069                               477                                                                                1 #STR204##                     0.003* 0.0032**                            478                                                                                2 #STR205##                     0.032* 0.0019**                            479                                                                                3 #STR206##                     0.023* 0.008                               480                                                                                4 #STR207##                     0.54*  0.026**                             481                                                                                5 #STR208##                     1.0    0.0034                              482                                                                                6 #STR209##                     0.41   0.0023                              484                                                                                7 #STR210##                     0.097  0.025                               485                                                                                8 #STR211##                     0.24   0.013                               486                                                                                9 #STR212##                     (10 μM) 39%                                                                        (10 μM) 77%                      488                                                                                0 #STR213##                     (10 μM) 96%                                                                        (10 μM) 87%                      489                                                                                1 #STR214##                     (10 μM) 51%                                                                        (10 μM) 52%                      490                                                                                2 #STR215##                     0.014  0.005                               491                                                                                3 #STR216##                     (10 μM) 82%                                                                        (10 μM) 83%                      492                                                                                4 #STR217##                     0.15   3.2                                 493                                                                                5 #STR218##                     0.14   (10 μM) 68%                      494                                                                                6 #STR219##                     0.11   5.8                                 517                                                                                7 #STR220##                     0.21   0.015                               518                                                                                8 #STR221##                     0.22*  0.0017**                            519                                                                                9 #STR222##                     0.12*  0.0032**                            520                                                                                0 #STR223##                     0.85*  0.0044**                            523                                                                                1 #STR224##                     0.11*  0.0028**                            524                                                                                2 #STR225##                     0.17*  0.0012**                            525                                                                                3 #STR226##                     0.43*  0.00042**                           526                                                                                4 #STR227##                     0.05*  0.0033**                            527                                                                                5 #STR228##                     0.025* 0.00067**                           528                                                                                6 #STR229##                     0.20*  0.006**                             538                                                                                7 #STR230##                     0.052* 0.001**                             546                                                                                8 #STR231##                     0.066* 0.073**                             547                                                                                9 #STR232##                     0.015* 0.004**                             529                                                                                0 #STR233##                     0.99*  0.002**                             530                                                                                1 #STR234##                     0.003* 0.0037                              580                                                                                2 #STR235##                     0.2    0.08                                581                                                                                3 #STR236##                     0.021  0.0053                              582                                                                                4 #STR237##                     0.13   0.014                               583                                                                                5 #STR238##                     0.054  0.027                               584                                                                                6 #STR239##                     1.2    0.48                                585                                                                                7 #STR240##                     0.28   0.083                               586                                                                                8 #STR241##                     0.45   0.23                                587                                                                                9 #STR242##                     0.057  0.022                               588                                                                                0 #STR243##                     0.040  0.012                               589                                                                                1 #STR244##                     (10 μM) 91%                                                                        (10 μM) 82%                      590                                                                                2 #STR245##                     (10 μM) 89%                                                                        (10 μM) 81%                      591                                                                                3 #STR246##                     (10 μM) 45%                                                                        (10 μM) 64%                      592                                                                                4 #STR247##                     3.3    0.24                                593                                                                                5 #STR248##                     0.21   0.042                               594                                                                                6 #STR249##                     (10 μM) 78%                                                                        (10 μM) 23%                      595                                                                                7 #STR250##                     (10 μM) 57%                                                                        (10 μM) 93%                      687                                                                                8 #STR251##                     0.002* 0.007**                             597                                                                                9 #STR252##                     (10 μM) 100%                                                                       (10 μM) 97%                      598                                                                                0 #STR253##                     (10 μM) 55%                                                                        (10 μM) 93%                      599                                                                                1 #STR254##                     0.046  0.014                               600                                                                                2 #STR255##                     0.42   0.74                                609                                                                                3 #STR256##                     2.4*   0.021**                             611                                                                                4 #STR257##                     0.5*   0.004**                             660                                                                                5 #STR258##                     0.073  0.064                               661                                                                                6 #STR259##                     0.057  0.057                               662                                                                                7 #STR260##                     0.04   0.035                               663                                                                                8 #STR261##                     0.009  0.025                               664                                                                                9 #STR262##                     0.12   0.048                               665                                                                                0 #STR263##                     0.056  0.039                               666                                                                                1 #STR264##                     0.16   0.013                               667                                                                                2 #STR265##                     0.17   0.013                               668                                                                                3 #STR266##                     0.17*  0.029**                             669                                                                                4 #STR267##                     0.071* 0.035**                             689                                                                                5 #STR268##                     0.085* 0.54**                              676                                                                                6 #STR269##                     (10 μM) 41%                                                                        (10 μM) 89%                      670                                                                                7 #STR270##                     1.1    0.29                                685                                                                                8 #STR271##                     0.061* 0.061**                             612                                                                                9 #STR272##                     1.7*   0.01**                              688                                                                                0 #STR273##                     0.059* 0.034**                             690                                                                                1 #STR274##                     0.22*  0.022**                             691                                                                                2 #STR275##                     0.072* 0.0029**                            692                                                                                3 #STR276##                     0.007* 0.004**                             693                                                                                4 #STR277##                     0.021* 0.005**                             694                                                                                5 #STR278##                     0.12   0.0017**                            695                                                                                6 #STR279##                     0.015* 0.0018**                            696                                                                                7 #STR280##                     12.5*  0.065**                             697                                                                                8 #STR281##                     0.62*  0.003**                             698                                                                                9 #STR282##                     1.3*   0.013**                             699                                                                                0 #STR283##                     (1 μM) 19%                                                                         (1 μM) 100%                      700                                                                                1 #STR284##                     (1 μM) 77%*                                                                        (10 μM) 100%**                   701                                                                                2 #STR285##                     0.34*  (1 μM) 100%                      702                                                                                3 #STR286##                     (1 μM) 9%*                                                                         (1 μM) 85%**                     703                                                                                4 #STR287##                     (1 μM) 35%*                                                                        (1 μM) 87%**                     704                                                                                5 #STR288##                     (1 μM) 100%*                                                                       (1 μM) 92%**                     707                                                                                6 #STR289##                     0.20*  0.006**                             714                                                                                7 #STR290##                     0.023* 0.041**                             715                                                                                8 #STR291##                     0.0078*                                                                               0.073**                             716                                                                                9 #STR292##                     0.002* 0.031**                             __________________________________________________________________________

Vasopressin V₂ Antagonist Activity in Conscious Hydrated Rats

Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound. One hour later, arginine vasopressin (AVP, antidiuretic hormore, ADH) dissolved in peanut oil is administered at 0.4 μg/kg intraperitoneally. Two rats in each test would not receive arginine vasopressin but only the vehicle (peanut oil) to serve as water-loading control. Twenty minutes later each rat is given 30 mL/kg of deionized water orally by gavage and is placed individually in a metabolic cage equipped with a funnel and a graduated glass cylinder to collect urine for four hours. Urine volume is measured and osmolality analyzed by use of a Fiske One-Ten osmometer (Fiske Assoc., Norwood, Mass., U.S.A.). Urinary sodium, potassium, and chloride are analyzed by use of ion-specific electrodes in a Beckman E3 (Electrolyte 3) Analyzer.

In the following results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity. The results of this test on representative compounds of this invention are shown in Table XIV.

                  TABLE XIV                                                        ______________________________________                                         Vasopressin V.sub.2 Antagonist Activity In                                     Conscious Hydrated Rats                                                                Dose           Urine Volume                                                                            Osmolality                                     Ex. No. (mg/kg) N      (ml/4 hrs)                                                                              (mOsm/kg)                                      ______________________________________                                         *               78     13.3 ± 0.3                                                                            229 ± 6                                    **              6      12.1 ± 1                                                                              497 ± 53                                                   4      12.4 ± 0.8                                                                            361 ± 30                                   ***             76      2 ± 0.2                                                                             1226 ± 58                                   1       30      2       1.1     1504                                           215     30      2       0.7     1520                                           3       10      7      15.8 ± 1                                                                              567 ± 33                                           3       8       9.6 ± 0.9                                                                            584 ± 56                                           1       5       65 ± 1                                                                               515 ± 79                                   4       10      2      16.9      571                                                   3       4       9.5 ± 1.2                                                                            646 ± 115                                          1       2       2       1129                                           5       30      2       7.7      955                                                   10      2       8.5     1079                                           6       30      5      17.9 ± 1.3                                                                            616 ± 87                                           10      8      20.4 ± 1.1                                                                            346 ± 25                                           3       4      15 ± 1.6                                                                              519 ± 30                                           1       2       6        970                                           7       30      2      12.4      815                                                   10      2       9        780                                           8       30      2       9.1     1010                                                   10      2       3.4     1211                                           14      10      2       5.2      836                                                   3       2       4.5     1000                                           82      30      2       1.7     1808                                           84      30      2       6.5      425                                                   10      2       4.4      416                                           85      30      2      12.5      383                                                   10      2       2       1123                                           87      20      2       4.3     1300                                                   10      2       3       1488                                           89      30      2       3.3     1320                                           91      10      2      12.5      414                                                   3       2       2.3     1267                                           93      30      2       5.1      594                                           96      10      4      10.3 ± 1.3                                                                            647 ± 63                                           3       2       4.4      716                                           116     30      2       8       1295                                                   10      2       5.5     1242                                           354     10      2       8.8     1010                                           356     10      2       5.8     1023                                           358     30      2       5.5      875                                           2       10      2       9.3     1015                                           9       10      2       5.8      702                                           99      30      2      15.2      334                                           467     10      2      18        365                                           466     10      2      14.1      522                                           17,160  30      2       4.1     1374                                           489     10      2       6.1     1194                                           490     10      4      71.5 ± 1.6                                                                            487 ± 38                                   590     10      2       3       1355                                           581     10      4       4 ± 1.2                                                                              941 ± 219                                  469     10      2      11.3      548                                           599     10      2      18        407                                           470     10      3      17        387                                           484     10      2       8        785                                           485     10      2       4        961                                           471     10      4      14.1 ± 1.9                                                                            507 ± 38                                   479     10      2       6       1042                                           482     10      4      22 ± 0.9                                                                              372 ± 17                                   54      10      2       5       1275                                           274     10      2       3       1177                                           465     10      2      21.8      361                                           480     10      2       8.8      827                                           528     10      2      11.3      647                                           529     10      2      10.5      569                                           520     10      2      18.5      394                                           519     10      2      19.9      399                                           523     10      2       5       1218                                           524     10      2      10        528                                           525     10      2      13        557                                           526     10      2      17.8      455                                           527     10      2      19.5      430                                           530     10      2       6        914                                           518     10      2      17.5      363                                           668     10      2      20.7      378                                           609                                                                            611                                                                            472     10      2       4.3     1453                                           582     10      2       9.5      604                                           473     10      2       2.3     1493                                           474     10      2      11.5      619                                           594     10      4       4.9 ± 1.2                                                                           1172 ± 182                                  586     10      2       4.3     1196                                           584     10      2       2.5     1718                                           595     10      2       8.3     1474                                           588     10      2       9.5      687                                           587     10      2       9        868                                           210,214 10      2      15.2      451                                           597     10      2       5.3     1250                                           517     10      2      14.7      411                                           217     10      2      14.3      466                                           585     10      2       3.3     1483                                           476     10      2       5       1233                                           593     10      2      11.8      577                                           596     10      2       2.8     1347                                           297(298)                                                                               10      2       7        796                                           477     10      2       5.3      701                                           478     10      2       3       1399                                           481     10      3      17.2      473                                           267,271                                                                        592                                                                            ______________________________________                                          *Water-load control                                                            **Waterload                                                                    Control + DMSO (10%)                                                           (20%)                                                                          ***AVPcontrol                                                            

Vasopressin V₁ Antagonist Activity in Conscious Rats

Conscious rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiltration with 2% procaine (0.2 ml). Using aseptic technique the ventral caudal tail artery is isolated and a cannula made of PE 10 and 20 (heat-fused) tubing is passed into the lower abdominal aorta. The cannula is secured, heparinized (1000 i.u./cc), sealed and the wound closed with one or two stitches of Dexon 4-0. The caudal vein is also cannulated in the same manner for intravenous drug administration. The duration of the surgery is approximately 5 minutes. Additional local anesthesia (2% procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an upright position. The cannula is attached to a Statham P23Db pressure transducer and pulsatile blood pressure is recorded. Increase of systolic blood pressure responses to arginine vasopressin 0.01 and 0.2 international unit (I.U.)(350 I.U.=1 mg) injections are recorded prior to any drug (compound) administration, after which each rat is dosed orally with compounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,180,240 and 300 min. later. Percentage of antagonism by the compound is calculated using the pre-drug vasopressin vasopressor response as 100%.

The results of this test on representative compounds of this invention are shown in Table XV.

The results of this test on representative compounds of this invention in which the dose, the maximum % inhibition and the time in minutes, are shown in Table XVI.

                                      TABLE XV                                     __________________________________________________________________________     VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                                   VAS Dose                                                             Dose      i.u./kg                                                                             Min Post                                                                            Control                                                                              Response Average                                                                            %                                       (mg/kg)   I.V. Dose Before VAS                                                                           After VAS                                                                           Change                                                                             Change                                                                             Inhibition                              __________________________________________________________________________     CONTROL   0.01  0   155   188  33  33.5                                                            156   190  34                                                        0.02      153   213  60  52.5                                                            165   210  45                                              Ex. No. 1                                                                            10 i.v.                                                                            0.01  30  161   165  4   4   88                                                          170   174  4                                                         0.02      159   170  11  8   85                                                          167   172  5                                                         0.01  60  157   173  16  16.5                                                                               51                                                          164   181  17                                                        0.02      157   182  25  20  62                                                          178   193  15                                                        0.01  90  151   176  25  21  37                                                          159   176  17                                                        0.02      154   184  30  27  49                                                          165   189  24                                                        0.01 120  150   173  23  22.5                                                                               33                                                          157   179  22                                                        0.02      150   191  41  37.5                                                                               29                                                          162   196  34                                                        0.01 180  148   177  29  29  13                                                          155   184  29                                                        0.02      151   209  58  48  9                                                           165   203  38                                                        0.01 240  146   176  30  27  19                                                          151   175  24                                                        0.02      151   200  49  39.5                                                                               25                                                          162   192  30                                                        0.01 300  146   176  30  32  4                                                           151   185  34                                                        0.02      151   200  49  39.5                                                                               25                                                          162   192  30                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,480 grams            CONTROL   0.01  0   131   168  37  31                                                              167   192  25                                                        0.02      131   190  59  50                                                              173   214  41                                              Ex. No. 2                                                                            10 i.v.                                                                            0.01  30  127   135  8   6.5 79                                                          175   180  5                                                         0.02      135   144  9   8   84                                                          178   185  7                                                         0.01  60  137   144  7   8   74                                                          172   181  9                                                         0.02      135   145  10  13  74                                                          176   192  16                                                        0.01  90  124   138  14  10.5                                                                               66                                                          173   180  7                                                         0.02      132   147  15  15  70                                                          173   188  15                                                        0.01 120  135   143  8   9.5 69                                                          167   178  11                                                        0.02      134   150  16  15  70                                                          170   184  14                                                        0.01 180  124   142  18  14  55                                                          165   175  10                                                        0.02      129   150  21  22  56                                                          162   185  23                                                        0.01 240  125   144  19  16.5                                                                               47                                                          164   178  14                                                        0.02      133   158  25  25  50                                                          167   192  25                                                        0.01 300  127   145  18  17.5                                                                               44                                                          159   176  17                                                        0.02      134   170  36  31.5                                                                               37                                                          163   190  27                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 430,480 grams            CONTROL   0.01  0   175   215  40  50                                                              175   235  60                                                        0.02      185   240  55  55                                                              200   255  55                                              Ex. No. 3                                                                            3 i.v.                                                                             0.01  30  180   190  10  15  70                                                          175   195  20                                                        0.02      180   205  25  23.5                                                                               57                                                          185   207  22                                                        0.01  60  185   190  5   12.5                                                                               75                                                          180   200  20                                                        0.02      185   195  10  17.5                                                                               68                                                          185   210  25                                                        0.01  90  175   185  10  17.5                                                                               65                                                          175   200  25                                                        0.02      185   195  10  15  73                                                          185   205  20                                                        0.01 120  170   185  15  20  60                                                          175   200  25                                                        0.02      175   200  25  32.5                                                                               41                                                          185   225  40                                                        0.01 180  175   195  20  30  40                                                          165   205  40                                                        0.02      180   235  55  55  0                                                           185   240  55                                                        0.01 240  165   195  30  40  20                                                          160   210  50                                                        0.02      180   225  45  52.5                                                                               5                                                           185   245  60                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,330 grams            CONTROL   0.01  0   170   215  45  53.5                                                            163   225  62                                                        0.02      185   225  40  52.5                                                            190   255  65                                              Ex. No. 3                                                                            30 p.o.                                                                            0.01  30  170   180  10  15  72                                                          155   175  20                                                        0.02      175   190  15  20  62                                                          160   185  25                                                        0.01  60  165   190  25  22.5                                                                               57                                                          150   170  20                                                        0.02      170   190  20  22.5                                                                               57                                                          160   185  25                                                        0.01  90  165   175  10  10  81                                                          160   170  10                                                        0.02      165   185  29  20  62                                                          160   180  20                                                        0.01 120  160   175  15  10  81                                                          165   170  5                                                         0.02      165   170  5   12.5                                                                               76                                                          165   185  20                                                        0.01 180  175   180  5   10  81                                                          170   185  15                                                        0.02      170   185  15  17.5                                                                               67                                                          165   185  20                                                        0.01 240  170   175  5   5   91                                                          160   165  5                                                         0.02      165   170  5   10  81                                                          160   175  15                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,340 grams            CONTROL   0.01  0   155   215  60  57.5                                                            165   220  55                                                        0.02      190   230  40  50                                                              175   235  60                                              Ex. No. 3                                                                            10 p.o.                                                                            0.01  30  150   165  15  12.5                                                                               78                                                          175   185  10                                                        0.02      155   175  20  17.5                                                                               65                                                          175   190  15                                                        0.01  60  150   160  10  17.5                                                                               70                                                          155   180  25                                                        0.02      15.5  180  25  22.5                                                                               55                                                          160   180  20                                                        0.01  90  145   170  20  65  81                                                          160   175  15                                                        0.02      155   205  50  40  20                                                          155   185  30                                                        0.01 120  150   165  15  15  74                                                          160   175  15                                                        0.02      155   210  55  45  10                                                          160   195  35                                                        0.01 180  145   165  20  20  65                                                          155   175  20                                                        0.02      150   190  40  35  30                                                          165   195  30                                                        0.01 240  145   165  20  22.5                                                                               61                                                          160   185  25                                                        0.02      155   200  45  47.5                                                                               5                                                           165   215  50                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 340,360 grams            CONTROL   0.01  0   167   209  42  35                                                              170   198  28                                                        0.02      170   232  62  54.5                                                            177   224  47                                              Ex. No. 3                                                                            10 p.o.                                                                            0.01  30  116   124  8   10  71                                                          172   184  12                                                        0.02      113   128  15  18.5                                                                               66                                                          168   190  22                                                        0.01  60  115   122  7   10.5                                                                               70                                                          170   184  14                                                        0.02      116   133  17  18.5                                                                               66                                                          168   188  20                                                        0.01  90  116   122  6   6.5 81                                                          134   141  7                                                         0.02      160   185  25  24  56                                                          167   190  23                                                        0.01 120  162   172  10  14.5                                                                               59                                                          165   184  19                                                        0.02      160   168  8   10.5                                                                               81                                                          161   174  13                                                        0.01 180  162   162  0   8   77                                                          164   180  16                                                        0.02      156   165  9   13.5                                                                               75                                                          163   181  18                                                        0.01 240  162   168  6   8.5 76                                                          170   181  11                                                        0.02      160   170  10  22.5                                                                               59                                                          175   210  35                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 380,360 grams            CONTROL   0.01  0   147   182  35  40                                                              136   181  45                                                        0.02      150   213  63  54                                          Ex. No. 3                                                                            10 p.o.                                                                            0.01  30  147   157  10  11  73                                                          132   144  12                                                        0.02      148   162  14  16  70                                                          134   152  18                                                        0.01  60  143   155  12  11.5                                                                               71                                                          136   147  11                                                        0.02      151   160  9   22.5                                                                               58                                                          134   170  36                                                        0.01  90  142   154  12  12  70                                                          133   145  12                                                        0.02      145   162  17  17.5                                                                               68                                                          130   148  18                                                        0.01 120  139   154  15  12.5                                                                               69                                                          133   143  10                                                        0.02      136   164  28  22.5                                                                               58                                                          127   144  17                                                        0.01 180  147   160  13  15.5                                                                               61                                                          120   138  18                                                        0.02      144   168  24  25  54                                                          122   148  26                                                        0.01 240  145   163  18  19.5                                                                               51                                                          122   143  21                                                        0.02      144   188  44  35.5                                                                               34                                                          126   153  27                                                        0.01 300  146   166  20  16.5                                                                               59                                                          124   137  13                                                        0.02      153   180  27  24  56                                                          134   155  21                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,390 grams            CONTROL   0.01  0   146   200  54  49                                                              139   183  44                                                        0.02      148   205  57  51.5                                                            146   192  46                                              Ex. No. 3                                                                            3 i.v.                                                                             0.01  30  143   158  15  15  69                                                          124   139  15                                                        0.02      145   166  21  22  57                                                          160   183  23                                                        0.01  60  143   161  18  21  57                                                          131   155  24                                                        0.02      147   185  38  29  44                                                          138   158  20                                                        0.01  90  128   148  20  12  76                                                          148   152  4                                                         0.02      154   188  34  28  46                                                          133   155  22                                                        0.01 120  137   155  18  20.5                                                                               58                                                          148   171  23                                                        0.02      138   161  23  18.5                                                                               64                                                          148   162  14                                                        0.01 180  146   162  16  21  57                                                          139   165  26                                                        0.02      148   179  31  28.5                                                                               45                                                          146   172  26                                                        0.01 240  142   166  24  32  35                                                          132   172  40                                                        0.02      126   145  19  27.5                                                                               47                                                          139   175  36                                                        0.01 300  141   162  21  19  61                                                          146   163  17                                                        0.02      146   179  33  30.5                                                                               41                                                          145   173  28                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 510,510 grams            CONTROL   0.01  0   140   175  35  47.5                                                            142   202  60                                                        0.02      155   194  39  49.5                                                            154   214  60                                              Ex. No. 4                                                                            10 p.o.                                                                            0.01  30  133   173  40  44.5                                                                               6                                                           139   188  49                                                        0.02      154   178  24  36  27                                                          153   201  48                                                        0.01  60  156   177  21  30.5                                                                               36                                                          142   182  40                                                        0.02      156   182  26  44.5                                                                               10                                                          145   208  63                                                        0.01  90  153   180  27  38.5                                                                               19                                                          141   191  50                                                        0.02      163   199  36  52  -5                                                          152   220  68                                                        0.01 120  164   198  34  32.5                                                                               32                                                          146   177  31                                                        0.02      161   194  33  50.5                                                                               -2                                                          146   214  68                                                        0.01 180  149   183  34  35.5                                                                               25                                                          141   178  37                                                        0.02      148   185  37  44  11                                                          141   192  51                                                        0.01 240  148   169  21  29  39                                                          133   170  37                                                        0.02      158   184  26  26  47                                      SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,510 grams            CONTROL   0.01  0   137   170  33  31.5                                                            139   169  30                                                        0.02      141   193  52  48                                                              122   166  44                                              Ex. No. 5                                                                            10 i.v.                                                                            0.01  30  141   146  5   5.5 83                                                          120   126  6                                                         0.02      143   155  12  13.5                                                                               72                                                          137   152  15                                                        0.01  60  144   152  8   7.5 76                                                          123   130  7                                                         0.02      144   155  11  10.5                                                                               78                                                          124   134  10                                                        0.01  90  148   155  7   9   71                                                          141   152  11                                                        0.02      146   155  9   8   83                                                          145   152  7                                                         0.01 120  144   158  14  13  59                                                          123   135  12                                                        0.02      148   164  16  15  69                                                          126   140  14                                                        0.01 180  143   156  13  12  62                                                          124   135  11                                                        0.02      145   164  19  19  60                                                          123   142  19                                                        0.01 240  137   155  18  17  46                                                          117   133  16                                                        0.02      135   160  25  23.5                                                                               51                                                          118   140  22                                                        0.01 300  130   161  31  30  5                                                           112   141  29                                                        0.02      139   181  42  39.5                                                                               18                                                          119   156  37                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,410 grams            CONTROL   0.01  0   143   189  46  36.5                                                            162   189  27                                                        0.02      151   195  44  42                                                              162   202  40                                              Ex. No. 6                                                                            10 i.v.                                                                            0.01  30  152   158  6   5.5 85                                                          157   162  5                                                         0.02      144   165  21  16  62                                                          147   158  11                                                        0.01  60  150   163  13  7.5 79                                                          177   179  2                                                         0.02      144   170  26  23  45                                                          162   182  20                                                        0.01  90  139   153  14  13.5                                                                               63                                                          155   168  13                                                        0.02      145   168  23  27  36                                                          154   185  31                                                        0.01 120  143   160  17  15  59                                                          154   167  13                                                        0.02      143   176  33  29.5                                                                               30                                                          151   177  26                                                        0.01 180  138   165  27  20.5                                                                               44                                                          152   166  14                                                        0.02      148   189  41  35  17                                                          157   186  29                                                        0.01 240  143   175  32  24  34                                                          163   179  16                                                        0.02      151   199  48  35.5                                                                               15                                                          166   189  23                                                        0.01 300  143   175  32  25.5                                                                               30                                                          165   184  19                                                        0.02      152   193  41  36  14                                                          173   204  31                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,520 grams            CONTROL   0.01  0   144   181  37  47                                                              134   191  57                                                        0.02      140   190  50  56                                                              150   212  62                                              Ex. No. 7                                                                            10 i.v.                                                                            0.01  30  141   151  10  6   87                                                          152   154  2                                                         0.02      147   162  15  7.5 87                                                          159   159  0                                                         0.01  60  138   143  5   6   87                                                          148   155  7                                                         0.02      136   145  9   8   86                                                          148   155  7                                                         0.01  90  134   147  13  8.5 82                                                          142   146  4                                                         0.02      137   149  12  12.5                                                                               78                                                          139   152  13                                                        0.01 120  132   142  10  9.5 80                                                          136   145  9                                                         0.02      134   150  16  13  77                                                          141   151  10                                                        0.01 180  136   151  15  17.5                                                                               63                                                          138   158  20                                                        0.02      136   158  22  23  59                                                          134   158  24                                                        0.01 240  129   146  17  20.5                                                                               56                                                          132   156  24                                                        0.02      131   157  26  30.5                                                                               46                                                          143   178  35                                                        0.01 300  128   146  18  20  57                                                          136   158  22                                                        0.02      134   151  17  23  59                                                          145   174  29                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 550,530 grams            CONTROL   0.01  0   142   191  49  37                                                              145   170  25                                                        0.02      152   213  61  51.5                                                            147   189  42                                              Ex. No. 8                                                                            10 i.v.                                                                            0.01  30  156   178  22  14.5                                                                               61                                                          145   152  7                                                         0.02      150   176  26  23.5                                                                               54                                                          139   160  21                                                        0.01  60  145   154  9   14.5                                                                               61                                                          150   170  20                                                        0.02      145   162  17  21.5                                                                               58                                                          158   184  26                                                        0.01  90  146   154  8   10  73                                                          160   172  12                                                        0.02      142   160  18  17.5                                                                               66                                                          161   178  17                                                        0.01 120  141   154  13  11.5                                                                               69                                                          156   166  10                                                        0.02      139   154  15  15.5                                                                               70                                                          162   178  16                                                        0.01 180  139   156  17  14  62                                                          157   168  11                                                        0.02      140   172  32  28  46                                                          158   182  24                                                        0.01 240  138   151  13  15  59                                                          148   165  17                                                        0.02      143   178  35  29  44                                                          152   175  23                                                        0.01 300  143   161  18  18  51                                                          147   165  18                                                        0.02      153   183  30  28  46                                                          157   183  26                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 585,450 grams            CONTROL   0.01  0   167   183  16  22                                                              162   190  28                                                        0.02      163   193  30  50.5                                                            154   225  71                                              Ex. No. 41                                                                           10 i.v.                                                                            0.01  30  153   164  11  12  45                                                          163   176  13                                                        0.02      161   194  33  23.5                                                                               53                                                          155   169  14                                                        0.01  60  161   171  10  9   59                                                          159   167  8                                                         0.02      156   172  16  18  64                                                          153   173  20                                                        0.01  90  154   169  15  14  36                                                          166   179  13                                                        0.02      151   179  28  22.5                                                                               55                                                          153   170  17                                                        0.01 120  150   160  10  14  36                                                          151   169  18                                                        0.02      149   163  14  16.5                                                                               67                                                          164   183  19                                                        0.01 180  153   167  14  13.5                                                                               39                                                          156   169  13                                                        0.02      154   172  18  21  58                                                          155   179  24                                                        0.01 240  151   162  11  12.5                                                                               43                                                          151   165  14                                                        0.02      156   179  23  23.5                                                                               53                                                          158   182  24                                                        0.01 300  145   160  15  15  32                                                          150   165  15                                                        0.02      150   180  30  27  47                                                          155   179  24                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,400 grams            CONTROL   0.01  0   164   209  45  47.5                                                            160   210  50                                                        0.02      186   229  43  51.5                                                            156   216  60                                              Ex. No. 82                                                                           10 i.v.                                                                            0.01  30  156   195  39  36  24                                                          152   185  33                                                        0.02      165   218  53  54  -5                                                          159   214  55                                              Ex. No. 82                                                                           20 i.v.                                                                            0.01  60  162   180  18  15.5                                                                               67                                                          147   160  13                                                        0.02      161   199  38  37  28                                                          151   187  36                                                        0.01  90  158   181  23  23.5                                                                               51                                                          144   168  24                                                        0.02      144   175  31  24  53                                                          143   160  17                                                        0.01 120  157   173  16  16.5                                                                               65                                                          143   160  17                                                        0.02      161   200  39  38.5                                                                               25                                                          152   190  38                                                        0.01 180  149   171  22  18.5                                                                               61                                                          139   154  15                                                        0.02      150   197  47  43.5                                                                               16                                                          130   170  40                                                        0.01 240  144   175  31  29  39                                                          143   170  27                                                        0.02      150   198  48  42  18                                                          146   182  36                                                        0.01 300  152   185  33  32  33                                                          136   167  31                                                        0.02      156   206  50  53  -3                                                          147   203  56                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470 grams            CONTROL   0.01  0   147   191  44  46                                                              163   211  48                                                        0.02      154   212  58  61                                                              160   224  64                                              Ex. No. 84                                                                           10 i.v.                                                                            0.01  30  146   165  19  10.5                                                                               77                                                          172   174  2                                                         0.02      152   168  16  14.5                                                                               76                                                          159   172  13                                                        0.01  60  152   167  15  16.5                                                                               64                                                          154   172  18                                                        0.02      158   201  43  33.5                                                                               45                                                          161   185  24                                                        0.01  90  144   158  14  13  72                                                          153   165  12                                                        0.02      152   173  21  26  57                                                          156   187  31                                                        0.01 120  150   166  16  19.5                                                                               58                                                          143   166  23                                                        0.02      150   175  25  32.5                                                                               47                                                          147   187  40                                                        0.01 180  141   168  27  24.5                                                                               47                                                          149   171  22                                                        0.02      148   170  22  31.5                                                                               48                                                          148   189  41                                                        0.01 240  131   154  23  26  43                                                          143   172  29                                                        0.02      149   186  37  37  39                                                          148   185  37                                                        0.01 300  137   161  24  22.5                                                                               51                                                          151   172  21                                                        0.02      148   193  45  43  30                                                          150   191  41                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 600,490 grams            CONTROL   0.01  0   144   165  21  26.5                                                            127   159  32                                                        0.02      147   190  43  35.5                                                            137   165  28                                              Ex. No. 85                                                                           10 i.v.                                                                            0.01  30  162   163  1   4.5 83                                                          119   127  8                                                         0.02      156   166  10  9   75                                                          130   138  8                                                         0.01  60  156   162  6   7   74                                                          124   132  8                                                         0.02      156   168  12  9.5 73                                                          129   136  7                                                         0.01  90  151   160  9   9.5 64                                                          125   135  10                                                        0.02      143   150  7   7.5 79                                                          124   132  8                                                         0.01 120  145   152  7   9   66                                                          123   134  11                                                        0.02      139   147  8   6.5 82                                                          127   132  5                                                         0.01 180  125   141  16  15.5                                                                               42                                                          118   133  15                                                        0.02      129   147  18  19.5                                                                               45                                                          106   127  21                                                        0.01 240  129   144  15  12  55                                                          107   116  9                                                         0.02      135   152  17  18  49                                                          108   127  19                                                        0.01 300  129   144  15  12  55                                                          107   116  9                                                         0.02      135   152  17  18  49                                                          108   127  19                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 540,530 grams            CONTROL   0.01  0   141   205  64  62.5                                                            138   199  61                                                        0.02      138   227  89  66.5                                                            143   187  44                                              Ex. No. 87                                                                           10 i.v.                                                                            0.01  30  136   210  74  50  20                                                          145   171  26                                                        0.02      157   227  70  57  14                                                          144   188  44                                              Ex. No. 87                                                                           20 i.v.                                                                            0.01  60  133   150  17  14.5                                                                               77                                                          143   155  12                                                        0.02      150   191  41  32.5                                                                               51                                                          143   167  24                                                        0.01  90  140   163  23  24.5                                                                               61                                                          141   167  26                                                        0.02      148   197  49  33.5                                                                               50                                                          145   163  18                                                        0.01 120  136   162  26  26  58                                                          146   172  26                                                        0.02      152   196  44  35.5                                                                               47                                                          150   177  27                                                        0.01 180  130   163  33  26.5                                                                               58                                                          139   159  20                                                        0.02      148   192  44  37.5                                                                               44                                                          142   173  31                                                        0.01 240  135   172  37  28.5                                                                               54                                                          132   152  20                                                        0.02      136   191  55  41  38                                                          133   160  27                                                        0.01 300  140   177  37  30  52                                                          128   151  23                                                        0.02      138   201  63  48.5                                                                               27                                                          134   168  34                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 480,550 grams            CONTROL   0.01  0   149   178  29  40                                                              158   209  51                                                        0.02      150   213  63  62                                                              161   222  61                                              Ex. No. 89                                                                           10 i.v.                                                                            0.01  30  155   160  5   5   88                                                          160   165  5                                                         0.02      160   170  10  5   92                                                          160   160  0                                                         0.01  60  160   170  10  7.5 81                                                          160   165  5                                                         0.02      155   170  15  10  84                                                          175   180  5                                                         0.01  90  150   155  5   7.5 81                                                          160   170  10                                                        0.02      150   165  15  12.5                                                                               80                                                          160   170  10                                                        0.01 120  140   155  15  15  63                                                          155   170  15                                                        0.02      140   170  30  27.5                                                                               56                                                          155   180  25                                                        0.01 180  135   160  25  25  38                                                          155   180  25                                                        0.02      140   170  30  32.5                                                                               48                                                          155   190  35                                                        0.01 240  135   160  25  25  38                                                          155   180  25                                                        0.02      140   170  30  35  44                                                          150   190  40                                                        0.01 300  130   155  25  27.5                                                                               31                                                          150   180  30                                                        0.02      135   170  35  32.5                                                                               48                                                          160   190  30                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 610,600 grams            CONTROL   0.01  0   144   190  46  48.5                                                            154   205  51                                                        0.02      150   220  70  62.5                                                            160   215  55                                              Ex. No. 91                                                                           10 i.v.                                                                            0.01  30  145   150  5   5   90                                                          150   155  5                                                         0.02      150   160  10  7.5 88                                                          150   155  5                                                         0.01  60  157   160  3   6.5 87                                                          155   165  10                                                        0.02      150   158  8   7   89                                                          155   161  6                                                         0.01  90  155   165  10  9   81                                                          152   160  8                                                         0.02      150   165  15  12.5                                                                               80                                                          150   160  10                                                        0.01 120  150   170  20  13  73                                                          140   146  6                                                         0.02      148   165  17  17.5                                                                               72                                                          142   160  18                                                        0.01 180  142   164  22  22  55                                                          143   165  22                                                        0.02      149   167  18  29  54                                                          145   185  40                                                        0.01 240  146   165  19  20  59                                                          129   150  21                                                        0.02      147   189  42  29.5                                                                               53                                                          135   152  17                                                        0.01 300  146   164  18  16.5                                                                               66                                                          146   161  15                                                        0.02      144   167  23  32.5                                                                               48                                                          147   189  42                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 560,530 grams            CONTROL   0.01  0   158   203  45  49.5                                                            154   208  54                                                        0.02      159   228  69  72                                                              160   235  75                                              Ex. No. 93                                                                           10 i.v.                                                                            0.01  30  160   162  2   2   96                                                          139   141  2                                                         0.02      157   162  5   4.5 94                                                          163   167  4                                                         0.01  60  154   154  0   3   94                                                          163   169  6                                                         0.02      161   166  5   5.5 92                                                          164   170  6                                                         0.01  90  150   155  5   5   90                                                          163   168  5                                                         0.02      154   162  8   7   90                                                          161   167  6                                                         0.01 120  151   156  5   6   88                                                          158   165  7                                                         0.02      155   160  5   7   90                                                          160   169  9                                                         0.01 180  151   161  10  13.5                                                                               73                                                          151   168  17                                                        0.02      151   164  13  15.5                                                                               78                                                          155   173  18                                                        0.01 240  145   158  13  13  74                                                          156   169  13                                                        0.02      148   166  18  17  76                                                          158   174  16                                                        0.01 300  146   158  12  12  76                                                          156   168  12                                                        0.02      144   162  18  18.5                                                                               74                                                          154   173  19                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 580,480 grams            CONTROL   0.01  0   155   202  47  45.5                                                            165   209  44                                                        0.02      160   225  65  61                                                              172   229  57                                              Ex. No. 95                                                                           10 i.v.                                                                            0.01  30  163   193  30  29.5                                                                               35                                                          168   197  29                                                        0.02      170   225  55  56  8                                                           170   227  57                                              Ex. No. 95                                                                           20 i.v.                                                                            0.01  60  154   171  17  15  67                                                          156   169  13                                                        0.02      160   177  17  19.5                                                                               68                                                          162   184  22                                                        0.01  90  154   168  14  13.5                                                                               70                                                          167   180  13                                                        0.02      158   177  19  24  61                                                          164   193  29                                                        0.01 120  147   167  20  24  47                                                          161   189  28                                                        0.02      153   174  21  28.5                                                                               53                                                          161   197  36                                                        0.01 180  146   168  22  23.5                                                                               48                                                          156   181  25                                                        0.02      154   189  35  34  44                                                          161   194  33                                                        0.01 240  151   168  17  21.5                                                                               53                                                          154   180  26                                                        0.02      153   189  36  34  44                                                          165   197  32                                                        0.01 300  142   165  23  24.5                                                                               46                                                          151   177  26                                                        0.02      148   193  45  37.5                                                                               39                                                          163   193  30                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,470 grams            CONTROL   0.01  0   134   163  29  32.5                                                            144   180  36                                                        0.02      137   193  56  57.5                                                            153   212  59                                              Ex. No. 96                                                                           10 i.v.                                                                            0.01  30  144   157  13  11.5                                                                               65                                                          143   153  10                                                        0.02      139   150  11  19.5                                                                               66                                                          148   176  28                                                        0.01  60  141   149  8   7   78                                                          149   155  6                                                         0.02      140   155  15  12.5                                                                               78                                                          148   158  10                                                        0.01  90  133   148  15  13.5                                                                               58                                                          148   160  12                                                        0.02      136   151  15  16  72                                                          146   163  17                                                        0.01 120  134   148  14  13.5                                                                               58                                                          146   159  13                                                        0.02      137   151  14  17.5                                                                               70                                                          148   169  21                                                        0.01 180  136   153  17  15.5                                                                               52                                                          140   154  14                                                        0.02      139   153  14  16  72                                                          136   154  18                                                        0.01 240  133   152  19  18.5                                                                               43                                                          138   156  18                                                        0.02      136   173  37  39.5                                                                               31                                                          145   187  42                                                        0.01 300  138   154  16  15.5                                                                               52                                                          137   152  15                                                                  147   184  37  42  27                                                          138   185  47                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,440 grams            CONTROL   0.01  0   158   181  23  29                                                              148   183  35                                                        0.02      161   198  37  48                                                              151   210  59                                              Ex. No. 116                                                                          10 i.v.                                                                            0.01  30  160   181  21  22.5                                                                               22                                                          162   186  24                                                        0.02      160   191  31  36.5                                                                               24                                                          156   198  42                                                        0.01  60  158   180  22  18  38                                                          156   170  14                                                        0.02      160   197  37  33.5                                                                               30                                                          160   190  30                                                        0.01  90  159   182  23  19  34                                                          157   172  15                                                        0.02      163   201  38  32  33                                                          162   188  26                                                        0.01 120  157   175  18  19.5                                                                               33                                                          158   179  21                                                        0.02      154   203  49  40  17                                                          167   198  31                                                        0.01 180  153   170  17  18  38                                                          157   176  19                                                        0.02      155   201  46  40  17                                                          176   210  34                                                        0.01 240  153   169  16  16  45                                                          156   172  16                                                        0.02      152   188  36  38.5                                                                               20                                                          156   197  41                                                        0.01 300  153   176  23  22  24                                                          127   148  21                                                        0.02      154   205  51  41.5                                                                               14                                                          163   195  32                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 460,570 grams            CONTROL   0.01  0   146   184  38  36.5                                                            156   191  35                                                        0.02      146   210  64  56.5                                                            160   209  49                                              Ex. No. 117                                                                          10 i.v.                                                                            0.01  30  154   195  41  36  1                                                           162   193  31                                                        0.02      154   220  66  63  -12                                                         162   222  60                                                    20 i.v.                                                                            0.01  60  154   182  28  36  1                                                           164   208  44                                                        0.02      157   197  40  40  29                                                          173   213  40                                                        0.01  90  158   174  16  22.5                                                                               38                                                          162   191  29                                                        0.02      160   208  48  46  19                                                          165   209  44                                                        0.01 120  151   171  20  23  37                                                          154   180  26                                                        0.02      150   183  33  38  33                                                          158   201  43                                                        0.01 180  141   168  27  26.5                                                                               27                                                          150   176  26                                                        0.02      143   185  42  46  19                                                          151   201  50                                                        0.01 240  139   168  29  25  32                                                          146   167  21                                                        0.02      143   175  32  40.5                                                                               28                                                          146   195  49                                                        0.01 300  137   164  27  26  29                                                          149   174  25                                                                  144   183  39  42.5                                                                               25                                                          149   195  46                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 570,460 grams            CONTROL   0.01  0   135   171  36  34.5                                                            121   154  33                                                        0.02      138   184  46  47.5                                                            156   205  49                                              Ex. No. 157                                                                          10 i.v.                                                                            0.01  30  136   175  39  26  25                                                          152   165  13                                                        0.02      148   199  51  38  20                                                          153   178  25                                                        0.01  60  150   179  29  26.5                                                                               23                                                          135   159  24                                                        0.02      160   191  31  31.5                                                                               34                                                          153   185  32                                                        0.01  90  145   167  22  21  39                                                          161   181  20                                                        0.02      148   185  37  40  16                                                          152   195  43                                                        0.01 120  136   161  25  26.5                                                                               23                                                          138   166  28                                                        0.02      140   183  43  39.5                                                                               17                                                          150   186  36                                                        0.01 180  131   164  33  32.5                                                                               6                                                           132   164  32                                                        0.02      137   185  48  52  -9                                                          140   196  56                                                        0.01 240  140   167  27  28.5                                                                               17                                                          155   185  30                                                        0.02      138   167  29  35.5                                                                               25                                                          143   185  42                                                        0.01 300  138   162  24  25.5                                                                               26                                                          141   168  27                                                        0.02      146   176  30  40  16                                                          156   206  50                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 400,470 grams            CONTROL   0.01  0   146   191  45  41                                                              161   198  37                                                        0.02      157   207  50  50                                                              163   213  50                                              Ex. No. 357                                                                          10 i.v.                                                                            0.01  30  144   159  15  16.5                                                                               60                                                          167   185  18                                                        0.02      145   169  24  16  68                                                          164   172  8                                                         0.01  60  156   160  4   4.5 89                                                          164   169  5                                                         0.02      145   159  14  10.5                                                                               79                                                          164   171  7                                                         0.01  90  142   153  11  8   80                                                          167   172  5                                                         0.02      143   154  11  10.5                                                                               79                                                          168   178  10                                                        0.01 120  140   151  11  8   80                                                          165   170  5                                                         0.02      136   139  3   6   88                                                          165   174  9                                                         0.01 180  147   154  7   9.5 77                                                          162   174  12                                                        0.02      142   154  12  11  78                                                          162   172  10                                                        0.01 240  145   159  14  14  66                                                          159   173  14                                                        0.02      157   174  17  14.5                                                                               71                                                          160   172  12                                                        0.01 300  148   164  16  16  61                                                          151   167  16                                                        0.02      148   169  21  16  68                                                          158   169  11                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 500,460 grams            CONTROL   0.01  0   139   190  51  36.5                                                            159   181  22                                                        0.02      155   212  57  39.5                                                            166   188  22                                              Ex. No. 358                                                                          10 i.v.                                                                            0.01  30  147   163  16  12  67                                                          161   169  8                                                         0.02      149   169  20  24  39                                                          162   190  28                                                        0.01  60  145   153  8   13  64                                                          153   171  18                                                        0.02      142   155  13  10  75                                                          160   167  7                                                         0.01  90  142   157  25  17.5                                                                               52                                                          156   166  10                                                        0.02      148   161  13  11  72                                                          161   170  9                                                         0.01 120  144   153  9   8   78                                                          159   166  7                                                         0.02      139   155  16  14  65                                                          155   167  12                                                        0.01 180  134   158  24  17.5                                                                               52                                                          147   158  11                                                        0.02      146   162  16  14.5                                                                               63                                                          154   167  13                                                        0.01 240  139   153  14  12  67                                                          143   153  10                                                        0.02      144   162  18  15.5                                                                               61                                                          145   158  13                                                        0.01 300  137   163  26  19  48                                                          137   149  12                                                        0.02      140   158  18  16  59                                                          141   155  14                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 520,515 grams            CONTROL   0.01  0   141   165  24  23.5                                                            145   168  23                                                        0.02      145   182  37  37                                                              153   190  37                                              Ex. No. 384                                                                          10 i.v.                                                                            0.01  30  145   157  12  9   62                                                          156   162  6                                                         0.02      150   168  18  14.5                                                                               61                                                          158   169  11                                                        0.01  60  151   160  9   9   62                                                          158   167  9                                                         0.02      152   162  10  10.5                                                                               72                                                          160   171  11                                                        0.01  90  154   170  16  12  49                                                          160   168  8                                                         0.02      157   177  20  15.5                                                                               58                                                          162   173  11                                                        0.01 120  149   159  10  10.5                                                                               55                                                          131   142  11                                                        0.02      150   162  12  11.5                                                                               69                                                          164   175  11                                                        0.01 180  150   162  12  11  53                                                          158   168  10                                                        0.02      156   167  11  13.5                                                                               64                                                          160   176  16                                                        0.01 240  145   156  11  11  53                                                          155   166  11                                                        0.02      145   161  16  15  59                                                          160   174  14                                                        0.01 300  148   162  14  12  49                                                          152   162  10                                                        0.02      151   168  17  17  54                                                          158   175  17                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 455,500 grams            CONTROL   0.01  0    96   135  39  36                                                              151   184  33                                                        0.02      131   154  23  36                                                              158   207  49                                              Ex. No. 407                                                                          10 i.v.                                                                            0.01  30  120   131  11  9.5 74                                                          150   158  8                                                         0.02      132   142  10  13  64                                                          153   169  16                                                        0.01  60  112   139  27  25.5                                                                               29                                                          150   174  24                                                        0.02      128   131  3   10  72                                                          154   171  17                                                        0.01  90  90    114  24  19  47                                                          152   166  14                                                        0.02      87    122  35  26.5                                                                               26                                                          154   172  18                                                        0.01 120  120   127  7   8.5 76                                                          145   155  10                                                        0.02      113   127  14  17  53                                                          147   167  20                                                        0.01 180  112   124  12  11.5                                                                               68                                                          141   152  11                                                        0.02      109   129  20  20  44                                                          139   159  20                                                        0.01 240  114   130  16  18  50                                                          131   151  20                                                        0.02      120   136  16  21.5                                                                               40                                                          142   169  27                                                        0.01 300  115   130  15  20  44                                                          130   155  25                                                        0.02      116   137  21  22.5                                                                               38                                                          136   160  24                                              SPONTANEOUSLY HYPERTENSIVE RATS n = 2 Body weight(s): 470,550                  __________________________________________________________________________     grams                                                                     

                  TABLE XVI                                                        ______________________________________                                         VASOPRESSIN (VAS) VASOPRESSOR RESPONSE                                         Ex. No. Dose mg/kg  Max. % Inhibition                                                                           Time (min)                                    ______________________________________                                          2      30 i.v.     74           120                                            9      10 i.v.     95           60                                             17     30 i.v.     50           60                                             36     30 i.v.     71           60                                             99     10 i.v.     76           120                                           210     10 i.v.     78           90                                            217     30 i.v.     57           90                                            271     10 i.v.     56           60                                            274     10 i.v.     59           300                                           465     10 i.v.     85           90                                            466     30 i.v.     94           94                                            467     10 i.v.     65           120                                           468     10 i.v.     68           30                                            469     10 i.v.     69           30                                            470     10 i.v.     87           180                                                   30 p.o.     69           180                                           471     30 i.v.     85           90                                            472     30 i.v.     36           90                                            474     30 i.v.     80           60                                            476     10 i.v.     78           30                                                    30 p.o.     19           180                                           477     10 i.v.     88           180                                                   30 p.o.     82           30                                            478     10 i.v.     76           120                                           479     10 i.v.     83           60                                                    30 p.o.     69           90                                            480     10 i.v.     29           300                                           481     30 p.o.     58           80                                            482     10 i.v.     40           60                                            484     10 i.v.     79           300                                                   30 p.o.     22           180                                           485     30 i.v.     64           60                                            488     30 i.v.     43           60                                            489     30 i.v.     39           120                                           490     10 i.v.     74           90                                                    10 p.o.     65           120                                           517     10 i.v.     81           90                                            525     30 i.v.     70           60                                            527     30 i.v.     85           180                                           528     30 i.v.     66           300                                           530     30 i.v.     89           120                                           581     10 i.v.     94           30                                                    30 p.o.     79           30                                            582     10 i.v.     75           180                                           585     10 i.v.     56           30                                            587     10 i.v.     75           60                                            588     10 i.v.     65           90                                                    30 p.o.     80           120                                           590     30 i.v.     89           120                                           592     30 i.v.     37           90                                            593     30 i.v.     67           60                                            594     30 i.v.     36           180                                           595     30 i.v.     44           90                                            599     30 i.v.     86           90                                            600     30 i.v.     78           60                                            ______________________________________                                    

Oxytocin Receptor Binding

(a) Membrane Preparation

Female Spraque-Dawley rats weighing approximately 200-250 g are injected intramuscularly (i.m.) with 0.3 mg/kg of body weight of diethylstilbestrol (DES). The rats are sacrificed 18 hours later under pentobarbital anesthesia. The uteri are dissected out, cleaned of fat and connective tissues and rinsed in 50 ml of normal saline. The tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.HCl, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 with three passes of 10 sec each. The homogenate is passed through two (2) layers of cheesecloth and the filtrate centrifuged at 1000×g for 10 min. The clear supernatant is removed and recentrifuged at 165,000×g for 30 min. The resulting pellet containing the oxytocin receptors is resuspended in 50.0 mM Tris.HCl containing 5.0 mM MgCl₂ at pH 7.4, to give a protein concentration of 2.5 mg/ml of tissue suspension. This preparation is used in subsequent binding assays with [³ H]Oxytocin.

(b) Radioligand Binding

Binding of 3,5-[³ H]Oxytocin ([³ H]OT) to its receptors is done in microtiter plates using [3H]OT, at various concentrations, in an assay buffer of 50.0 mM Tris.HCl, pH 7.4 and containing 5.0 mM MgCl₂, and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg; 1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml of buffer solution. Non-specific binding is determined in the presence of 1.0 uM unlabeled OT. The binding reaction is terminated after 60 min., at 22° C., by rapid filtration through glass fiber filters using a Brandel® cell harvester (Biomedical Research and Development Laboratories, Inc., Gaithersburg, Md.). Competition experiments are conducted at equilibrium using 1.0 nM [³ H]OT and varying the concentration of the displacing agents. The concentrations of agent displacing 50% of [³ H]OT at sites (IC₅₀) are calculated by a computer assisted DON-2 program (LUNDON SOFTWARE INC., Ohio, U.S.A.).

The results of this assay on representative examples are shown in Table XVII.

                  TABLE XVII                                                       ______________________________________                                         Oxytocin                                                                                Dose         % Inhibition                                             Ex. No.  (μM)      at 10 μM                                                                              IC.sub.50                                      ______________________________________                                          3       10           90        0.36                                            4       10           98        0.66                                            6       10           92        0.35                                            7       10           97        0.13                                            17      10           31                                                        36      10           67        2.45                                            54      10           94        0.16                                            85      10           98        0.46                                            93      10           87        0.06                                            96      10           94        1.2                                            160      10           31                                                       164      10           67        2.45                                           210      10           64        4                                              214      10           64        4                                              215      10           74        0.57                                           217      10           87        1.2                                            274      10           95        1                                              297      10           76        4                                              298      10           76        4                                              298      10           76        4                                              416      10           44.6      7.4                                            417      10           21                                                       418      10           39                                                       419      10           28                                                       420      10           16                                                       429      10           11                                                       430      10           16                                                       431      10           18                                                       432      10           19                                                       433      10           12                                                       435      10           10                                                       436      10           32                                                       441       1           22                                                       443      10           70                                                       444      10           21                                                       448      10           11                                                       449      10           14                                                       450      10           22                                                       451      10           43                                                       452      10           36                                                       455      10           75        2.9                                            460      10           77        3.1                                            461      10           44.6      7.4                                            462      10           14                                                       463      10           55        8.5                                            464      10           55        8.5                                            464      10           71        2.4                                            465      10           93        0.033                                          468      10           96        0.26                                           469      10           96        0.265                                          470      2.5          92        0.22                                           471      10           99        0.35                                           472      10           0                                                        473      10           20                                                       474      10           18                                                       476      10           94        0.82                                           477      1.25         97        0.029                                          478      1.25         97        0.04                                           479      10           76        0.15                                           480      10           98        0.15                                           481      10           88        0.24                                           482      10           97        0.126                                          485      10           86        2.2                                            486      10           18                                                       489      10           44                                                       490      10           99        0.3                                            491      10           46                                                       517      10           91        0.32                                           519      10           97        0.48                                           520      10           79        2.2                                            524      10           84        1.8                                            525      10           98        0.28                                           526      10           97        0.47                                           527      10           92        0.45                                           528      10           90        1.17                                           529      10           92        0.45                                           530      10           99        0.31                                           538      10           90        0.9                                            546      10           91        0.99                                           547       5           97        0.26                                           580      10           79        2.96                                           581      10           99        0.2                                            582      10           96        0.675                                          583      10           61        4                                              584      10           26                                                       585      10           70        4.7                                            586      10           61        4.7                                            587      10           56        8                                              588      10           90        2                                              590      10           12                                                       591      10           29                                                       592      10           41                                                       593      10           82        1.1                                            594      10           19                                                       595      10           49                                                       596      10           86        4                                              597      10           42                                                       598      10           2                                                        499      10           92        0.35                                           609      10           66        2.7                                            664      10           95        1.4                                            665      10           97        1                                              666      10           83        2.1                                            667      10           89        1.6                                            676      10           32                                                       ______________________________________                                    

The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include but are not limited to the following: salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds can also be used in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo.

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol(e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. 

We claim:
 1. A compound selected from Formula I: ##STR293## wherein; the moiety ##STR294## represents a fused pyridine ring or fused substituted pyridine ring optionally substituted by (C₁ -C₃) lower alkyl, halogen or (C₁ -C₃) lower alkoxy;the moiety; ##STR295## is a five-membered aromatic (unsaturated) fused nitrogen-containing heterocyclic ring wherein D is carbon or nitrogen, and E, and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C₁ -C₃) lower alkyl, hydroxy, COCCl₃, COCF₃, ##STR296## R_(b) is independently selected from H, --CH₃, or --C₂ H₅ ; q is 1 or 2; R₃ is the moiety ##STR297## wherein Ar is a moiety selected from the group ##STR298## and X is selected from O, S, NH, --NCH₃, or --N--COCH₃ ; R₄ is selected from H, lower alkyl (C₁ -C₃), --CO-lower alkyl (C₁ -C₃), SO₂ lower alkyl (C₁ -C₃), or the moieties of the formulae: ##STR299## R₁ and R₂ are, independently, H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy, or halogen; R₅ is H, (C₁ -C₃) lower alkyl, (C₁ -C₃) lower alkoxy or halogen; R₆ is selected from:(a) moieties of the formula: ##STR300## wherein cycloalkyl is defined as C₃ to C₆ cycloalkyl, cyclohexenyl or cyclopentenyl; n is 0-2; R_(a) is independently selected from H, --CH₃, --C₂ H₅, ##STR301## R_(b) is as hereinbefore defined; q is 1 or2;(b) a moiety of the formula: ##STR302## where R₂ is as hereinbefore defined; (c) a moiety of the formula: ##STR303## wherein J is R_(a), lower alkyl (C₁ -C₈) branched or unbranched, lower alkenyl (C₂ -C₈) branched or unbranched, --O-lower alkyl (C₁ -C₈) branched or unbranched, --O-lower alkenyl (C₂ -C₈) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, or --CH₂ --K wherein K is halogen, (C₁ -C₃) lower alkoxy, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: ##STR304## wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C₁ -C₃)lower alkyl, hydroxy, --CO-lower alkyl (C₁ -C₃), CHO, (C₁ -C₃)lower alkoxy, or --CO₂ -lower alkyl (C₁ -C₃); and R_(a) and R_(b) are as hereinbefore defined;(d) a moiety selected from those of the formulae: ##STR305## wherein R_(c) is selected from halogen, (C₁ -C₃)lower alkyl, --O-lower alkyl (C₁ -C₃), OH ##STR306## q is 1 or2; R_(a) and R_(b) are as hereinbefore defined;wherein Ar' is selected from the group: ##STR307## wherein W' is selected from O, S, NH, N-lower alkyl (C₁ -C₃), --NHCO-lower alkyl (C₁ -C₃), or NSO₂ -lower alkyl (C₁ -C₃); R⁷ is selected from H, lower alkyl (C₁ -C₃), halogen, --O-lower alkyl (C₁ -C₃), or CF₃ ; R⁸ and R⁹ are independendy selected from hydrogen, lower alkyl (C₁ -C₃), S-lower alkyl (C₁ -C₃), halogen, --NH-lower alkyl (C₁ -C₃), --OCF₃, --CN, --OH, --S--CF₃, --NO₂, NH₂, or --O-lower alkyl (C₁ -C₃); R¹⁰ is H, halogen, or lower alkyl-(C₁ -C₃);and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
 2. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, ester or prodrug form thereof, and a suitable pharmaceutical carrier.
 3. A method for treating disease in a mammal characterized by excess renal reabsorption of water, the method comprising administering to a mammal in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, ester or prodrug form thereof, and a suitable pharmaceutical carrier.
 4. The method of claim 3 wherein the disease in a mammal characterized by excess renal reabsorption of water is congestive heart failure. 